REFERENCES

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                                              REFERENCES

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                      PUBLICATIONS FROM THESIS

FULL LENGTH PAPERS:
  l. &4gLE!@l              Asd Hugin Sh.h. Sy.d Dilmw Ahn.d .nd DaElnsha! J.b..n
      Hdan(2010).
      Prer..dr. .ll@c of.qrcoB tui,t .xn .r tftn Sa bucllton (Htppophd thahtui.hs
      L. W TwkltMtca) on hdop.ridol indwd orcf.cial dyslin€sia ed l)€@&l
      al|ErioN in thc atrilim.
      M€d sci Modir. vol 16 (7): (Acccprcd ed Publish ir JULY 2010) (hp.ct r.dor
      l.sla).

 2. E!4!!&!99!, Muhdnd Abdll Hd@ sd DaEIrBhe ftt€n tLl!@ (20 | 0).
    Acutc arlninisdition of d@piE dd rirFddonc .ltcFd dop@irc Ddabolis n@
    in 6t €udrlc tho in nwl.s @ub.ns: . dd-epoM rldiotuhip.
    sci Phm. 78 (2): ii Pr.33. ttoirl0.379lsiplum.0907-20 (A@.pLd dd hblbh in
    JUNE 2010; rEilabl. on Jourlt's Hm.!!s. a "anicL in pB").


 L Frrt B @L Anbren H$u! Muhdmad Abdul Hdcn                                    od Dornshrn.bben

      DoFEht    eficrs of .loapirc .nd dspcridorc on parrcn of b6in Egjoml slonin
                   d
      ad dopmie nctabolis &d on l6ti El.r.d !o .xE pytuidd tuncdc i! Dtt.
      Acla Phm 60 (2). (A@Fcd &d Publbh in,t E2010).

 4,   f.ri.t     E .ooL Asd       Hlein     Shah, Sycd   DilEw       Anr*d od D@t!sh& Jabe.
      Halen (2009).
      or.r $ppr.hs .1io. of Sa b@Wbft (Htwopha. Rhawi bs L. qp. TEk stati.d)
      &uit qt!.t rEdifics hdoFidol indu.cd beh.vioEl tleicns ed imt!€s b6ir
      sdrdin tu|llolish.
      .touNl of Food &d Dos An lris vol.             17. No.   4. 257-263.   0r0...   F.etor Oatl).

 5. F.ri.l B.lool Sh@ib Ahhrd ed Dddtl'sle .l.ben H.icn. (2009).
    Diet ry suppLhdrllionr of miio &idr Evid.M ror onec.d *blon6gic
    n4$o6 fouowins hrlopdidol wirhdraqd in 6t m.dial pGtoital @ri.x.
      J.   Coll. Phrsicid S!rr. P.l.l9(3)r139-145.

 6. &4gDs@! .rd Dur)'!he Jlhar Halam (2008).
    SeDlonini^ Fc.pror agonin in $e cxpBioo of b.lEvioal dopditurgic
    suF&sitirity b sbchrcnic hdoD.ridol tsrd nls,
      P.k   J   Phm    Sci, Vol 2l (4): 4l I -420.
z       Eruo ShiE!\ Kho.d F.rn.t Brrml snd Dadtltlh& Jalen Halam (2005).
        Irctte in S€otonir-lA r@pro. EspoBircns folo*irg brloFridol wilMn$al.
        ,ou. Of Bsic rnd A@li€d Sciel6, vol- 2, Na l, 45-54.

8.      DaDrnsh& .,. Haleen! &44!d!91Nldia H. Kh.tr, N@r KMil, Ob6!d Ali, z.s.
        sairy, and M.a. Hd€m. (2002).
        DiiIeFnc.s in the effects of halopdjdol md clozapine on brain @lonin od
        dopani.e ieuboli$ and on lests eht d to .xtlpttuirlal nsdioG in 6ts.
        Mcd. S.i. Monit 8(9)r BRl54'BR36l. (l6p..l Ldor r.514).

9- D.Ethshe           J. Hdc€o.    Falrr      B.r@1.   Nnli. H. Kho, N@r Kmil, O&id Ali,        Z.S-
        slit !d M.A- grl.o.         (2002).
        DoD€min   /   S@ionin            !,rd Extlptmid.l
                                nekloli!. dio                        .ffca   of   clozliE   in Ers.
        J.cnll. Phlsicidsurg. PaLoclobcr, l2{10). 58&592

10.     Em      Shine., Quor-Dl-Ai4     EshrLD!@! zdd          s. sai$   dd Dasl(hshs l.     Hal@n
        (2002).
        Neu@hcmical .f€cts        of 8-nydexy-2-(din-l4yldino)teiralin ir         dr   iljct€d with

        Pot J   Phm    Sci. Vol. 15 (No. 1), pp. 7l -82.


I   L   Asa Kh!4 Ft.trt    B.tool €!d D@lnrhe J. Halen (2001).
        B€h.!io6l cff4is of 8OH-DPAT in sinrlc .dd epered halop€ridol traLd ots.
        P'r J Phm S.i. vol.l4(2); July, rp 9-17.

12,     f.r!.i  B.lool. Z.S. Sairy, MA. Haic.n 4d Ddarhshd J. Halem (2000),
        N€mch.nical .nd extralrlmidd €fret! of .9?ic5l de@lepti. cloapirc in ol9.
        Pal ., PhM Sci. J&ury, vol. 13. (No. l ), pp. 47-55.
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      Acute Admlnistration of clozapine and
 Risperidone Altered Dopamine Metabolism More
   in Rat Caudate than ln Nqcleus Accumbens!
          A Dose-Response Relationship
    Farhat AAroor-' I, Muharnmad A. Ha!EEM'?, Darakhshan J, HALEEM I


'Depr oi B'on.dh3r Engii.lnng. str syed   uiiwdiy or En! i4diq .id T4
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epH]Nryenbd26'2009
                                     oorgno'9/oph:mjgoz,o
o B.rod   cr ,1,   ri@ns Osretr c]lisd. AF.lh.iorv.rr.9lr.srMan n b     B .   vi'nna. Ausda
                                    buca undd o. r.nr of rh. crc.rs
{hipltr€ri@nmoi..oaric€ns,hrB          04, rhicl' pcmiE rGnrided se. d
in dy medium. pmliden he onqinar Wr     6 p6r.r1y   d.d.

     Abstract
     The prc*nt study omp.r4 lh€ emapyEmidd and neurochemiGl effecls ot
     clozapine a.d ispeidon€ n Et @ud3le (colpus $natum) a.d nucleus
     a@nb€ns (v€nt€l slialum) dGedependenlly AnimaB injeded wilh
     cl@apine (2.5, 5.0 and 10.0 hgfiq lP) o! nsp.ndore (10,2.5 and 5.0 mgn(g lP)
     ,n aclre @re eqificad t h laler to @llecl bEin samd6 EnrapyEmidal side
     etrecrs (EPS) ln  lehs of l@omotor aclMry and @ialepsy ree m@irored in
     eacn anima afid the drug or vehicle administaiion. Mdimum catalepdc
     poieniia s @re lound only at high doss ol clozpine (10.0 ng/ksi60%) and
     nsp€ don6 (5 0 mg/kg: 100%). N.lrocn6m 6l $limat oG werc caflied oLn by
     HPIC-€C Eoth drugs ar ar dosas signifi@.rry (p<0.01) ine€*d rhe
     conc6nrE0on or homolan llc acid (BVA), a merabolire or DA, n rhe .audare
     nucleusand dec€ss€d in nucleB acclmb€ns. LevelB ot Oihyd rory ph€nyl..alic
     acd (ooPAc) esnir@nty (p.0.01) inqea*d in rhe caudare by clozapine
     adminsl.alion and decr€a$d in lhe iuceus acdmb€ns by the admi.istration
     of both drugs Ln a dosed€pefd.ni m6nn6r. s-Eydrcxyi.doloaclic .cid
     (s-fl,'A), the p€domi.anl m€l.bolile of BBrctoni. signinc..lly decro.sd in lho
     €udate and nuc€ls .ccumbens in a 5imilar laehion L€vel! of tryplophan
     (TRP)wer€ r€mained insignlica.l i. €udate a.d nucreus a@lnbens by the
     inteclions of two dtugs n c.qdate clozapin6 End speidone admnisirations
     sgnlicanty (p<001) deceased HVNoA 6to and inc€.sed DoPAC/DA Eto
     m nucl€us accuhbens at al doss Thelndngsslggesttheeviden@lorDA/s
     HT r*plor inle.act on as an imponant link n the @6r incidsne ot EPS The
     posibl€ roe ot seroton njaEcepto6 in ih€ p.thophysiology ol schizop h6.ia iE




Atypic.l anllpsychotics . Extrapyr5mid.t 3id€ eltects      .   Dopamine   D2 €eptors .
se.obf n,^ €€otors . sohizoohrgnir


 schEoph€nia s a clnlcal syndrome with dveB6 hanitestations. Dop6mne (DA) o,
 rc@ptor anl.aconism is posiu atsd ro b€ . key b Entipsychdic Effcacy in rh€ }6.rh6nl ot
 *l'zopt.na lll l/pEat .nLps/choric d-Jgi w.$ a h,gh qrapylamdst motq sde
 etrec6 (EPSj I'ab'lry maket r-c€a$ €ftaotLt€. dopan'ne r ri€ aJdatepuhnen.
w\ile atypi4L anl'psvchol'c drugs u$ a ow hcioe@ ot Eps h.ve te$ ponoLncd
 sbmultu-g adiors oa @rou3 su aEt dooar,ne [2,3) Th€Gloe, I hss b@n 6(€gsied
rhar fte EPs iabiiry o. anlpsychol'c oruse {ApD) ,s conotaled wirn lhetr .b t y b i;;ease
e{r,aerL ar dopadi^e i. rhe eld.te-pulafen l3l The caudrre nucteus is hrghty
innefraled by dopam'ne neurons Thos n€urons oignare ma,ny lrom lhe €n!.al
iegmentll drea (VTA) a.d the substarlE rEr6 paB @op.cl. (SNc)
                                                                       14,. ft€re ae d$
.oo(onarnp6 trof vanous a$@ialion 6ni6 Nucleus accumbens lNracl E.rcuE.
basr_s.ngria strudurE probabty mediating EPs ot typ.@t anlpsytuuc dtugs lq.
 In@oe, he pBst srJdy soughi to d.lMin€ whe'|a 6xr@Iurar doDanr@ h tE
tlAcc mighl @ a tudh{ ndieror to difeFtiai6 nd@hemret acloE ;t tvoel and
alypi€l .nbpsychotic dtugs The abrt y ot antips-ychorrc d^ros to ah +HT; eertol
                     wdety sugossied to @ [rbL{e to ther rherapernic prcFlt4 lq
Atypi€l antipsychotic drugs rotaGd to ddaptna, improve psy.h@b, cognition anil
n€atve symptoms, whil€ p@ducing miniFar EPs, in palienG *nh schizophre.ia [4. This
appea6 to be @diared mainry through |h€ @mbi.ed sf.cl ol elarivetv mor, ;orot
blekade ot s'HIr reep{ors, toeled on corncat and hippoempat qtutamatergjc and
GA&cdgic neurons, as well as cetr bodies oI $e o*olimbic end ns@ni€t dopamine
(DA) neurcns, 6.d weaker btockade of 016€ptoG in rhe vonrrst and doet srriatum and
pydm|dal nelrons in @dd a.€.5, as stt as rh€ el bodies or oA neurons
                                                                                F, BI. rhe
iipli€liors  of EPS r€ouct'on rouch v'nu6 y d6ry dom6,n ol pahotogy ,n sch;ophr€nE.
rfcruong shon. a.d orgren nov€me d'sod€B negarive synproms, non@mdBne,
rersose E!e, @sriLve dysfutlron and dysp.ons l9l -iE ,trpotunt goat or lh6 pl@nt
rsead o. arlp'@r n€urotept 6 is to devetop nov6 conpound,s) wr anLpsychotrc
DoiBnlia wilh a ow in.idan€ ol EPs

A najody ot schizophen c patients Gepofd to ctassi€t neurotepuc drugs which ae
b€1i6r'€d ro acr .rg€,y via oroaEoe ot oopahr. {OAr O, ,6epro3 i- im6c slruclur€g
I-01 Hoseve.5 3 9d(a.t o.ooon o- do -ol j€spono ro co.venlon.tD. e(eplo. btosrs
d',9)or sho* a rather nconp €E r.o.Ep€-trc €lfect oai'cJtE yon nega[r'e crd.ognit,v;
synprofstrrl A- e(5n'natio. of ct n c.t tireraLre sho$s rar h.toperco. s r'e{ Lkety lo
produe EPS, clozapin€ is reativety $ ikety and sp€ridon€ b sonewharmitd in tems ot
rhe p.odlclion th$e eliecre l12l In conp.neon wirh ctassic.r neuroteptG atpt€l
antpsycholic drugs such as for ex5mpe ctozapine a.d isp€ido.e hsve bo6n found (o
           Re   sronsh,p or cLozap,ne   ,id   R6oodd




pos*s idproved       etlicacy dgainst negalive symplofralology and €use a .educ€n
inciden@ ol EPS in cinically efe.live dos6l13l. The presenr work was undeiaken in an
atlefrpl to garn tunher rnsights inlo the mechsnisms of aclion ol a9pi€L anlipsycholic
druas as an i@n wilh row propensiry bwards EPS in rats Cr@pine, the fiBt of the
.typic.l anlipsycholic. has ben rcpoded lo b€ .ffetive in appoxinaiely one third or two
ihid ol pateds with treatment eesrant di*ae I12. 131 The arypi€l is reponed to be
etfe.tiw lor lhe t earment ol bolh positiw and ne!.tiv. symproms of $hizophroia. ll abo
plodues 3mall€r EPs lhan lypiel neubl€pric. Hower, cl@apine has lhe pol€nlj.ltor
talal adve6e etlet agr.nuLoqlosis 1141, . sudd€n dop in *hie cdl 6uni trFt @uld
leave lhe paiienl vulneabl€ lo ov€dnehing int dions I15l Obviously, a Ooal ol dr€nl
neurcLeptc €s€rch slo devalop ant'Fychotic compounds with low incidence of EPs.nd
agEnulocylos s o.e ol fie approach€s i. lhls.onbn has be. lo delemne
.euochem cal/ phamaco oqical corelales ol c ozapme and olher atypicalne!rc|€pb*. A
distingurshed element or rhe pha,macology ol coz.pine is
(5-hydrorytryptamlne; 5 H-l) receptors parlcla y s-HTn, s'HTrc and s-HT,a F@ptoB
116, 14 Trie alypdal has le€f arinily tor doFmn6 (OA) O, r{epto6 lh.n trsditio.al
antipsycholcs 14 111 Alhough crozapino is recognized as lhe protolypa atyAcal
rntipsychotc drug, there are no weld.lnBd c te a lor cassirying ndly d.velop€a
antipsychor's as alyplQL MeLl:er [12] suggeglod d€fining 3n anlipsychotc as atyp el
 ba*d on anralonistic acnons al borh, o, and sHT, re6ptorc as wel as c'nLcalcite a ol
 minLm. induclion oi EPS al therapeutic dosd

The prFent @ntribu( on iocu*s on $e poseble ole of dilfe€nt s'HT reeploB rn lhe
modulalion ol atypi€l neuroleprc mech.nisd of aclion olher than dopamlne eBptors
Folldina the discovery of sHT, (n@ temed sHTr) r@pto6. was cpofted thal *v€61
n.urclepii6 bound ro borh sHTa and D,              [12, 131. Rispendone provided tuiher
didene that    potem 5HTa anlagoni$ '@ploF fith miHer D, antago.ism I12,131
                                          @mbned
mulred in signifi€nlly improved clinical propeni$ 112,131 Inde€d. in addiron lo
su@sstuL lreatnent of the poslive symploms, isp€ndone narkedly imprcv€d tte
nelative symptoms ot scnizophrema wlh a l@ lL.bilny oi EPS 111-161 Risp€ridone a
beEisoxdol denvatue, is an antipsycholic agent, which @mbines polenl serolon n 5HT,
and dopamLne D, receptor antalonism [14 151 .nd has ben inlrcduced i. lhe wake or
clozap ne induced toxicity Mo@vd cLincsl studies have revealed thal ispdidone
displays a beneficalantpsychollc action improving bolh posiliva and negatLve symplomE,
*h lB havins a ow propensity ro ndu@ EPs 116 171 Besids s-HTra.d DA-D,.e@pto6,
nspeidoneexhibls ralher hqh gli nily ior @nlklor adr€.erg c and Hr hislamino @@ptors
and a moderale affn ty for o, sdrenerqic receplo.s [12.14-16]. Tlssue measuGmenls of
Goione DA a.d s-HT melabo rsh in tho rat b6in have i.deted lhat ispe.idone afibcis
Di luriover in both mesolmbic and nigrc$iatal tehinal rcg ons and,lo some ened, also
tHI metabo sm n rh€* larsel areas l12l
The   am ol the p.esent study wa3 ther.lorc, io @mpaE lh€ dos+espon$ etbcts of
clozapine and spendone on enrapy.amldal motor funct o^s and on oA melabol8m in ral
4udale and nucleus 3@mbens Homovanillic acid (HvA) and dlhvdroryphenvl a@lic
.cid (DoPAC) are lhe pGdomrnant metabolit$ ol oA, Theefo€, in lhe p6eni sludy
efecls of d@aDine and .isoeddore are aL$ @mpaed on HVA/DA and oOPAC/OA Etios
in eudale and nucleus a6lmb€ns of . 6t b@in
                            r   saroo M A Ni&nandD   I   Hareem




Matsrials and Methods

The prot@l for expeimenlanon was approv€3 ..d p€domed rn srricl a.cordane rith
lhe Glide lor lhe Care and U* ot !.bo6tory A^imats (nst'tute of LaboEiory Animl
R.eour@s on Life Scien@s. US Narionat Re*amh Councit 1996) and the haii|lllion.l
A.im.l ElhL6 commin€ {aEc) Mate Albirc-w3r.r rars wrh an aveEge reighl or
1AOt20 g, purchased rrom Agh. Xhan Univ€6[y (AKU) @e aed m siandar! dia and
waret ad tibilun The animats we€ g@p-hou$d two 6ts per €9e) in an
envirc.mmlarry @nvolled room (ahbi€nr lempeEture 2412.c and retative humidity
5515%) on a 12:12 h Light/ da.k cyce (ights on at 7:oo a.tv ) A s-da, a*lim.tiz.lioil
p.nod w* alowed befo.e anlma s wer6 u*d in €peiments. Afrer ltris penod, and 24 h
                             the a^idats reE indivdlaty holsed in an envnondent.ly
conlrolLed tesl room in rranspare.r Pe6per cages (drde.sons 26x26x26 cm wxLxSi
Th€ guideLines or rAEC. Pakislan lhe governin! body ior anmat e&enmentatio.s in
Pakielan were slriclly adhered to durnq the whote animatexper


Clozapife (sisma) was dissotved n a minimlm votlme or 01 M a@tic acid a^d pH
sdjusr€d ro 6s by NaoH and diut€d with physioogicat sune (0.9% NaCD ro
@nce-lrtron o' 2 5 ng,Tl. 50 ng/tr a.a .0 0 ngh.,P,. votLne\ oi tmAg body
rergnr xspenoore (Jdnssen) wzs drseotved 0.4v bnaric acd rno pH corLsled lo 6.5
by N.OH a.d diiuled wirh saline to LLre dBired 'n
                                                @n@ntrat ons ot i .O mght, 2 5 mgr'd and
5! mghl lP n volLm6 of 1 0 rukg body @rgt^l Conrro a^hats                   equai votum.
or Ehicre (0I ld a@ric acd,0 I M NaoH anror0.4 M tana c aod '@ved    and et,E n the rEto
or 11 1: 8) The animals re€ iniecred in a batan@ d6isn betw@n lcoo and 1t:@ h_
Molor adiviry mo.iro, ed lol 10 min slcn,ng 10 min aier inler,ors catatepsy €15€cb ol the
crugs @e s@red 'or a d1 oll lime ol 3 nh sEn'ng 30 m'n post Inle.tions and 3nrn.t!
@e k'lled to ollecr brainsa60les t hanerd'6drons

Das.-Dependehl Efiects al Ctaapine and Risparidone @ Laworlon
Molol@laied efecrs or  rr  orugs de 6 nonnored      Pe6pex acr v,ly @ges. Anh.tsE€
                                                 '.
r.nsf.n€d n Pe'soe, .cuv rr e!€s (26126^26 cn) wrF e.w dJsl @vsed loo.15 min
b6loro nj6ctn9 lhe saline or drug Exp6dmeni was coiducred in a *pa€t6 quiet room
Molor actvty h the acrivity box w.s monitor€d lidef wht€ tght as numbeF oi cag6
crossi.gt'0 n .  ralrg     0- n'r oost'1j€cr ong n.n gro-ps ot,rE,. a oa arco d6i9n


Det   Depehdenl EfraoB al Ctozapne and Rispendo@ oh Catatepsy
C.l.repsy defined as rhe a*eplanc€ .nd etenxon ot abnoma posrure. was mEasued
by m.ans ol a bar lst Bar tesl dol€minations wer6 caded oll by gedty Gmoving .ai3
(^:12) trom rhetr hofre €ges and pacing [\6d lo.€pas over a hdizonlat bar, tued at a
n6ight ol10 cm yirh heads ot animats lpwa.ds on an inctined surra@ al an angte ot 60.
wiln lhe hLnd limbs abducted 14, 131 TrE |ap* ot trne dunng wh'cn lhe anim.t etained
this posilion was .e@ded by reasunng lhe time lrom the pta@menr of the €t until
ehovd of one ot ils to€pes An animat to be tested was otaed on an inclined sud.e
(26 x 40cm 60'rncLinatoi) lor cul olt time 3 mn. A conlro ral changes its posrlDn
immediately on the nclinato^ Tme (sec) as dtug or salne mlected anidas emainad
immobi€ o.lhe nclinaton was mon|toEd. An ma s nol mov ng on the sudEc€ !p to 3 mLn
wee kept back in the r €a6 Calaleplic scoe ms €lculaied as {Latenc} ol mov€m€ni
(sY   dl-offlime (180 sD 100
N.utochemi.i An.lysis
Dlsc:li6                Nuclt* A@unbqs
            al Caudate and
Saline, clozapne or ispeidone qected anim.ls were kilea        t   h posl inj.ctions   lt€
dissecl on prc@dur€ was ess€nt a ly sam€ .5 desqibed bero6 118, 19) a trosh b€in       M.
diDp€d nice-coLdsaifeandpacedwlhitsvenl.a sidoupLnlhemoded@!lyolabr.in
sLi@r. Fne ishn! Ine wi@was n*ned inlo the slots oi the slic€. to give      c    or2 mm
thickness lhe sice conbini.g cald.le and nucleus accumbens was translercd to a
glass plate kepl on ice Punches of 2 5 mm diEme€r wee made bilal€rs ly in lhe upper
and lNei sides ol the srice lo collect lhe desired brain ego.s The sliatum de kndn
as sliiale body, neosriallm or sl ale nuclels is a sb@.li6l (ie . inside. €tl€r than on
rhe oLrlside) pad or lhe blen@phaLon/eebtum lt is lhe frajor         3lal'on of lhe bael
                                                               'np!l
ganglia system. In pimales (including humans) ihe stfatum is divded by a while matd
t€cl caled lhe interna capsule nio t@ sectoB el€d lhe cardale rucleus (co?rs
 sttiatun) and n@teus accunbens (rentzl striatun). The corecled brain Egions w@
mmediately sloed tor lhe  bosenr amne assay at -70'C ror lhe eslmation of DOPAC,
DA HVA and s.HlAA         Levels by Hgh pedomance lqld chrodaio!€phy with
eleclrochen ca deteclion (HPLc-Ec) h8l


                                        @e enE ied wilh 1:o plol peGnlodc.ttd
Biogenic amin6 and lhen major m6t bolii.s
(Hcloli 70 %) r.om br.in n$uo punch.. (< 25o !9) usins a timpr. on*i.p smd.
pGparalion derhod (re) a 5 rrm (panicb 3iz€) oos @lum. (..0 mm id. and 2s0 nm
Lensrh) was used Mobie phase conp sed or proponions or melh..ol (c&oHi 14 %),
ocvlsodum sulphare (oss 0 023 %)and €thylenediaminetelr.acol c acid {EoTA:0.0035
%) n 01M phosphaio buffer of pH 2 9 was passed lhrough the coLum. at conslanl flow
rale (1 O fr/mn) with the hep of waleB 510 HPLC plmp (walers colpoEton, us)
Electroched cal detection was acheved on sch'dadz! L-Ec 64 detector (shimadzu
Corporatiod, Japan) at an operating potential of 0 3 v Tryptophrn was detemi.ed Ln a
*p.6re tun ar an op€rali.s potentar ol 1.0 v 08, 19).

ResulE arc Dresented as mea^s 1 s o slatisliel analysis was perlo.med usng oneway
ANOVA (.nalyeb ol vai.nce) and Poslhojcodpaien was done by lhe Nsman_Keds
te$ pvalues< 05 wee co.s'dered slalislcally signili€nt


Figure 1 shows the dosej6ponse elalionship of c @apine and nspendone on l@omolor
acltiry and caraleptic potenrial in .ars. ANovA (df 3,12) showsd signifi€nl efie.ls ol
dspeddo.e (10, 2s and 5.0 hg,ks) on motor aclivjly (F=657 p<001) and etalepsv
(F=226.9 p<o.oi) Ellbcts ot clo2apine (2 5, 5 0 and 10 O ngr'kq) on molor aclivity (F=8 0




                               s. nhrm 200\ 7\ /XY   XxY
p<001)and €ralepsy rF:g 8p<00t)@ea,$sgnife Fbsl xoc an.tysis snowed lEl
100% c6laeps' @cu ed ony .r . doe or 50 mg/}g ot nspendo.6 and 60% at 1OO
mg/kg ot cozapine clozapne dd nor deceas aclvty al a do$ of 2.5 mq/q but
d.crc5s€d ir ar dos6 of 5.0 nq/ks and 10.0 mg/kg No el. epsy was ob3€eed ar orh€r
d@es 0t clozaorne a.d iso€ done


             +Cl@pjn.       I0.0,2.5, t 0.10.0 ng   lgl md.d s      1:,3     t   a   m X.ui.
               Fft.p.ndo.    (0.0, 1.0.2.q   5.0 m9 klr m|.iad .t   t   ri   a r or    x.et




                       i
                      F-\F\I
            E.

                     Catalepsy


           330
           B. s0




Fb. r.   Oos+6pons. gtteds ol clozpine and i5p€ndone on lo@motor activity a.d
         €ialepric porstisl in Ets varues a€ mean r so (h-12) signin@d dilG66
         by NMan-K4b lesl 'p<0.05, ':p<0.01 as @opared to @sp6ctiv6                            $lic
         rrealed €c lollMng ANOVA.
             R.b'ih!t"p   or   croaFe   dnd    REF.6m
                                                                  'n
                                                                       c.de d                Nuce A@mb.n3



                    +cl@!iie       10,0,   t5, t0,   10,0   rs   te1 mrnrd      ft   1,?,3   t 4 oi r.rh)
                    +Rilplrrdor.     10.!, 1,0, r.5, 5,0    h! |!r     nartad   d i,a3 r I or nr t)
                               DOPAC                                                            OA


                                                            iaso

                                                            3ra
                                                            I100
                                                             350




                                                             g
        ;




            Oos-espof* eftu 6 of c oz.p n. End ispe done on oOPAC, DA, HVA €nd
            s.HrqA i. r.l @!date. Vaiu6.ts m.an 1SO (n:12). Slg.iUenr difiscn@3 by
            N4man-Keuls t6l'p<0 05, -p<0.01 as @mpared to Gsp€ctive satin+treat€d



Figure 2 sh@i lhe dosrrespone eiecls ol ctozaDine and .soe done on the taels ot
dopam ne (0A), m.t.bolil65 dlhydrcxyph6nyt.@lic .cid (DOPAC) .nd hohovaniltic E id
(HVA), and s'hydroxyindoreacetic acd (s-HtAA) in ihe @udare nucteus. ANoVA (dI3.12)
Bh@edsigniflcanl ellocts ol clozapino on lh. .v€ts or oA (F=129.7 p<0 01), nVA(F:30.7
p<0.01), DoPAc (F=6 3 p<0 0s) and s-HtM (F.-16 p<005) Elfets ot.rsDeidone w6E
elso rgn'r'e    ror HVA      / I p<OOs)                                (i=12
                         'FtHtAA (F:1.2 Ef.bc|s ot n<pendo.e o. DApoJ h@ p>O O5l,
DoPAc (F=1 1 p>0.05) and                   p>0.05) reE nol sisniiient         analysis
sh@ed effecrs of ftpeddone on DoPAc changes @e nor signrfi€m Rars ihjecred wnt|
2.5 m!r'kg and 5.0 mqn(g exhibibd p6noun.6d 2-3 folC inccass in HVA @n6t€tion
and l're* incG5ss wee also @mp.rabl€. HVA ldels @16 abo inqeaed tott@ing tha



                                   so Phrm 200\                  7/   Ar-\M
                            F   B.bt   r]| A.   }l.tn   .nd D. J.   Hakm


adninkL5rion of d@pine and thE inqeas mdinun at a d@ of 5.0 mo^g. tv|anfrln
incr3.s ol HVA wc. ge.l* in ru!.ridoi.          cl@dn. inj€cted animts. Th€
@niEtion of DOPAC .l.o iffi.!€d toldng u. .dnini.tEtion ot do2.pr@ .r a d@
                                           'l.n
ql2-5 d!/kg and s.0 ms/kg ooPAc b€t. dd @r          .t ei.t.pto!6ilic do$ (ro.o
                                             'ncr6s
dE/tt) ol cle.piF 5-HlM r6v.l! i@3€d toltung 0F .dminut .um oi high do; oa
i+6noone bu      uE nq63s mc nor sirit5ent cdM6.iy, doz.eine .dmirisfrton
did d@s.d 5-H|,AA @@nrraiion               6t
                                   ar hioh d@ or tO.O mg/q. ft€ d.d.E .3 not
.'Enifent at d6.6 ol 2.5 nEL/kg and 5,0 mg/kg                       s6
                                                     signifi@nt {p<0.01) d      b.
ol.l.9log€nic d@e ot 10.0 frg/kg.


                      +trod. 0|'r{5r,nrqtlmrdrtl'r.rr{|l
                      +iirfrdd    04   rl2iir4 tl rrbd. tr:r.fl r{it
                          DOPAC




         s116
                                                  2n
         ir!0                          )
         g|0o                                     E10
                           .<-I -



                                           ]
         !
         6ro                                      ;   r!0


         I
                                                  !,o
         5lo                    ..)               j'

Flg.3.       Oo€*stone      6,f.cts ot cl@apim a.d dlo.ddon. on OOPAC, CrA. HVA srd
             tHlAA in ..t nucleus a@uhbd3, Vd@ a€ rean I So (n=12). Signifenr
             dilteEn@ by Neh.n-Keuls t6t 'r<0.05, ..p<0.01 .B @mDared to 6sD.<ds
             elin+lroaied 6t5 foll@ing aNova.



                                s.i'Efr20ox'7xx)(x-'J00(
                R.|donslipolcM'neandRlgi&


Figur€ .l shows re dose esoolse eri€cls or ctozap'.e and rbpenoor on lh€ tdets ol
OOoAC 0A -vA €nd 5- M,n -at b s'..-c.!e accurbe.s. i.vOvr .Ot I r:r sno*O
Bignifcant 6fiecr ot.leapine on ooPAc (F=64 5 p.oo1), oa (F=156 p<oo1), HVA
(F=19 5 p<0 0l'.1d s.HlM tF"1! 5 p<0Orrco-@nr?hons Efiecrs otlsp€noo.;wEG
signrcanr lo' DooAc,f- 2 5 p<001)and HVA \F=278 p.o otr No-sgnf,ca{ 6ft crs
d n6pendoae were obsetoed.or oA (F=17 p:005) a.d 5 r{AA rF=346 p<00t) posl
noccohpsnso. sho@ lhar ct@ephe sig^ii€.lty (p<o01) d4@sed @ncst6loB ot
OOPAC. HVA a^d $HtM
                            'n
                               a dGedepe^deal                         n.rn
                                                          Le,ets ot DA lgn,fienty
(p<0.01) esr$cntly IncEased at dG* or 2.5 mg/rg and to o mg/kg of de5p,;e Le6t;
ol DA and tHlAA efraned hsE^i1€nt at a[ lne do*s ot nspet|do@


                    +Clozlii.   {0.0, 2.5,5.0, 10.0   i{    rtr mrkd d   1,2,t   I I d X{ie)
                    +RL!.ridoi. ([0    1.0, r,5,   t0 n0    k01   mrrtd 6 1i3    e   l oi   Xdj!
                         CAUDATE                                    NUCLEUSACCUMBENS




          3
          i,                                           ;l
                                                       e,



                                                                     I{UCLEIJS ACCIJf,BEI{S


                                                       !m
      €                                                !
      :'                                               Em
      l*                                               6-




FlO. a,        Dose€pon*    ellects ol cto2ap nE and nspeidone on Tryptoph.n, HVA/OA
               .^d DOPAC/DA Elios in 6t €ud.to and nuctous a@mbens Values a6 tu$
               r SO (n=12). Siqnifi€ dm.@nc. by Nsman Keuts test 'p<O 05 -p<O 01
               .s @mpaEd to esp€clNe sal ne-tr6at6d .els foLldins ANovA.
 Figure a   shM
              lhe d6A'espon* efeds of ctdap,ne and dspendore on lhe       of      t*ts
rvF{ophan cnd rhe elios of HV&OA and OOPAC/OA ,n the rcr €udate dnd nude6
&@mbens. ANOVA (df 3,12) pedomed           o
                                      @udar6 daia sh@ed insigniti€r eried of
cl@aFne,(F:2,1 p0.05) and nspendone (F=46 p<o 05) ior IRp iNovA tdt 3,r2)
penorred on dala oI nweus rccumbens 6tso showed ,nrgn,lie efled ot;@pin;
(F=0 49 ooo-5) a^d nspdidone (E=332 p>oosl br TRp.b,b a@tyz6lor €;d€
snd^€d qignifi(dnt €1.cts ot cdap'n6 for HvAoa rF=151 p<0.01) 5nd nspend@
(F=33 2 p<O 0ll Data on nLcteus €eurb6.s sheeo
                                                     sign,fced €ffet d c %pne m
DOPAC/OA 6ro {E=tol, D<001r a.d nspe oone (F:945 0<OO.r. poy ,@;nrysis
shored thar the caudate do or HVA/DA deceas.d Bignfcanry (p<o or) rn a d;+
dependenr manner. conversey eves ot oopAc/oa rslio w.re signiticanly (p<0.01)
rncrea*d n iucleB accumbens by alt rh€ doses ot ctozap ne and ispertdone.


In     fe
        pe>eal s.rdy dryo'cal a.t,ps)foxc d.Jg3 or.o<a,eo 56cono ge-eralion
                                                           .ohpe.senr5c;u, ow
rc.deG 6f Fos                                                                  9
                                               r.r dero, srar€ anlpsycnor- .d,v,ty.
Managen€nr o'enEpy6n'oa s.de eff*rs (Eosr s a naF, co-em or ctn,...3 who us
.nlrpsyc'olcdtugs T5e rcdene ot foror s de e.lecls 3do*oepelde.r - he orsrnctio
beiieen ryoi€ ano .rypica anr psychoxc orug. ha3 ana n€d . @nsde,cbre ,mportrE
w Nlo'eover, the trllzdo? hyoorh*b has.rlfloure! o the d€vetopmenr ot mGt of
$e @renr SeneEUm of alypEl a.t'psychoLc agenrs ,.duohg risp€ndone, da@p,re,
qudap'ne. zip@i(rone. ngtperone and reGp.ron€, €,tolsh,ch he€ a h€he, aftn yfo.
5Hr, rhan ro' D? reeproE F6 27-311. Aryp€tiry           b€n .scibed io sHTt Cl
.@godsh hd may be mvot!€d wilh lhe anlpsrd|olE ^as [2. 201. rhe ryp@t €fleca ot
                                                    efi@t
etmh6tefing a DA-D? ecepto, antagon,st is a supAessbn ol sponranous tocmo{or
ba\:{ior a^d el'orfion ol a srale rnM as e|.repry in tabdarory animats 14,221 In 0E
pcenl slrdy. all tE dos6 ol ctdapne a.d nspendone @ u$d re€ lound to d(ree
hoior sclivrty in a do*depe.de{ manner (F|9 I ) ao$ drugs we,e tou.d catateptogenjc
ory d hrgh dog H@evd, erels ot bolh dugs on to@moror act,v,ry ,n c tcm ar
envronme.lre€ compa€ble.t a llhe dos€s
A major finding ol the pre*nt study is lhar acute admi.istration ot nsDeddofe €lativ€tv
unilormly in@ases DA etease and metabotism h lhe caudate relion ofEt brain. tt is nd;
genetslv ageed lt.r cLi-icc rosponse to neJrosprcs s assoc'als wtF !..nc.ecs h
HVA (oncerlrard 1241. T-e p oposeo n€c-6n'sr or FVA ch5n96,.votves.cr,,t€
blockade oi p6 and poslsynaptc O, receptoE in caudaie The p;synaplic btockade
ncrcases the amolnt of DA rceased on subF€qu€nt action pot€nli€ts. bu,i becals o,
poslsynapt@ reepioa ae also bocked, acut€ 0A l6nsmssto. is aitenualed
                                                                            tn addirion
 I s po,sb,€ rhat the 'e,arve lacl o. EPs noto etiocls wrh ctozao,re ald iroeioon;
sdmn6t6lron m_ ihe present sludy cold b€ Et.t€d to Nvo-My nreractio. ot dru96
towads OA and tHT @6pto6

ll.s   suggesred   rln
                    the oGsenr,'-o,.gs r"d lheagents i.o6esr19 dop.f,.e Icrsm$ion
hh.b'ts aeLrol€pic.nduc@ €tE epsy Th€ c.uo.re .nd .uct6
lhplicai€d as lhe m.jor brai. struclu€i invo v.d in €.tiplyc.hotic induced eratepsv, which
eppears due to the b ockade of dopami^e neurolEnsmbeio. Aninat studr.s suggesl ftal
ite nlcreus aelmbens Ls the citi€t region in whicn bolh typicaj and alypiel
            !!l!9:!ID d c or.pne r-o Filp,iio


a.l'psychotic dru93 ererr lhen an psy.horic efbcls [25]. t was shoM tn ea.ty srudid that
adminisrEilon oa a.tipsychotic dtugs increased OA lumrer in at brain 1251. i.ater studi6,
ge@€Lly .ddr6s€d OA €lea*, show an increase in DA rct€se in regrons cn in OA
reminars 123, 251. h has ben shoM thar brocl.d€ or pe and poslsymptic eefloE by a
si.qre i.j*rion of neu.oreptiG J€ads lo   .. i.c€.*   in re spike discha€e oi n6ur;n.
berong ng lo th€ nigctriatat syslen ot rhe 6r b6tn tt has been suggested ihar ins6.ed
oA release i. lhe €udale lnder lh6 inftu€nce of                     .an nake a d€init€
cont bur o. to lhe tomarion of atyprcat ph.macotogic ^elroteplics
                                                      p.of es ol rhese substences due to
conoerrlo- bet*ee- u a eeased Teoa@ a^d neu.ot6plc<            a  ^e everof poslsynaflrc

Tie preseni study shows rhat adm nts(raion ot bolh ctozapinB and rtsDe.done incr@sed
HVA concenrEllon n lhe caudalt (Frq. 2) R'sper done was moE eftedLv€ than cto2apire
in prcdlcing this effe.r in r}le €udate reOLon. OOPAC the olher md.botite or OA
hc'edsed .t                     ooss ol ddap're wheeas nspendore dd nor aner
             ^on€ldreplogen'c
oOPAC @n@nvaron h rhe @ldaie s.H[qA brets rer€ d€cE;*d .t eratepiogsrc
dose (100 nO/kg, ot cozdphe and nonc.l.tepiogen ! doss (10 & 2.5 mgi*t of

 signillclntly decreased levets ol DOPAC and HAV in rhe nuctew accumbens dos
deoende.tlr lFg.3,. 5-rAd ev66 we,e rso srg e y oecreas€d oy ctozapne
                      a do>edep€ndenl r..i.. Cal:leobgelrc do.e \.0.0 mg/}g) of
oo2aprc sg-icanr, nrr a*d oA teves                                   ov€..t dodcl ol
cloz3p ne and isperdone adminisliarion suggesls lhat DA met.boism n eud.te region
was moe EsponsN€ in evaluating the sl.t€plrc potentiat oi the drugs as comp.Ed to
nlc|lus accumbens. Bolh dtugs dd nol atrer tevets of TRp tn eud.le and n!d6c
a@ufrbens How@r, signif@nl dosedepende d@€as rere ob*ded in eldate
HVADA 2XoforrNng the adm'nistr.hon ofdoEprne.nd Bpeddore on $e other hand,
DOPAC,DA 6tio         lhe .ucteus a@mbens qee s'gnftenily i^(eased .r a the do*s ot
                   'n
do7:pre and nspeddone (Fig 4). lhe oesenl c*tts ctso sl.@ Lhal .tdap,ne,nduc€d
inc'eases o. DA metabot,s cjg€ry lare pa@ n the @udaG rF.n,n rh€ aucttu6
ac_ufbe_s compaGob efie(6 o.cozapr a-d rcpendone o. oa nel.bot.sr sre al
least pctly €ip           n,ens o.rae...dvrEs at DA aro 5-.i- c@plo-s Ctozapre hs
                  'cable
a rower Eflinlty for D, reeptoB and ispef done has high afinity ior s-HTr receptoE. In
el o d- a.1dic.ie rhat Lto--o'1€ is.pp-or LJretr eupolell al D, a.d D? re@p.ore
                                                                                 I24.
                                    mp ic.red n he rtuhan.s o, acl'on o, cozap,ne. Tne
dcs   LrA hrgh alhjly lo. D, l€epro6. rrsher
                                                    rhan ,ts afin,ry tor D, eeplo; 127,.?sl
Another d slinguished te.rue ot [le phamr-@togy ot c@apine,s ! n,gh anrnny t;
sroron,n 66pr4 panicutady s-HI,A.nd 5-HT:c sit6 This ph.ma@togic.t pbtir€ ot
|ne drug is otlen linked wirh irs lheEpeutic prorite and tse. incidence or Eps as obsqaed


Therc rs .ow considerab e evidenc€ from sNdies of schizoph€.ia and oths fons ot
ps croses €! 3.1e p!, Fo*s ano L.DooA p5voos65 rh.r. n-rb* ol rtyp,@l
an os,.-orc.€€.ls such:s (tucp.€ arJ.spe"oole -.ve.tso beer lolnd to nave
greater alt nity lor s-HT:a than D, re@ptorc irr vt@ afd aE more efi@! ve with fewef side
ere,G Tl-e seotol€.Sr efed> o,c,@ap, J atso h.ve b"en enprsrz€d as Dossbty
be'.g I aled lo lhe Jn q-e o'n.kt fdralrr. snc o' .to7.p ne tJ't a.d €en v ,t saa
sulgesGd lhat the s-HT?t O, bnding 6tio coutd be usd to dbt'nguish belw€s rypiel
and atypi@l anlipsycholE i32l A de@a* tHt tunover by d@pine i5 exptiebte in
l€ms or dru$ modede stlinily for tHT,^ .ecepro6 [32, 33] Antjpsych.trctik€ effe.ts ot
clozapfie .re sls oien expraLned in tems of s-HTr^ asonist .crivity ol the dtug I33l.
s-HTi^ agonisls decrcase 5-HT llmover . va ous b6n reg ons beue or rh€
slimuallon or rcceprors ocared on certbody dendites [34]. Th6re i6 evtdence rhatrHT,^
agoiisl aclivily is involved I clo2:pin6s beneficia clin car profite .nd ower inciden@ ot
EPS Thus poslsynapt c s-HT'^ @@ptors we.e up €gulaled in pGimonem *hzoph€nic
parienrs 1341. 5-HTd ago.isrs have ben shown ro revee hatope dot-induced catatepsy
1351. A comp..i@n ot lhe ettects of two dr!03 3h@s thal an incGas in fWA
@ne.lraiion in the caudar€ (Fiq 2) and ,n increas i. DoPAC/DA 6 o in nud*
eunbe.s (Fis 4) may be taken as a.euocheoicat profr e ot avpicat, ct@apire tike,
adNty Olher autho6 have.epolcd siqnilicanl nc@ases ln caudai+putamen vo um€s in
an'mars Ecerviig €rher hloperldol or cloz3prne when @mpare! with co.lrot animats
lollow n0 €ishi monrhs or drug adnhsrEron 136l Lt is suggesred rhar rhe neuroptasric
 esponse ot lhe stalum iolowng neuroLept'c €xposuG cau$s voLum€kic inc@ases,
whereas alypLcal annpsy.holics afi*l the basal gsngLis diffeenlialt slggesti.g that such
difle€nlial rcspones may b€ due lo both lhe phama@togi€t propenies and the retati€
doses ol lhe alypiel agenls

h   enclusio., lhe pesent stldy shMs xiai adninist€tion ot bolh ct@aphe aM
  speidone inceased DA m€l.bollso more h c€udat€ than in nucteus accumbens in t
doe-depend€nl ma.ner. Cons€llently, olr tndngs demonslrate a phamacotog€l
prolilo ol rspordone, as reflecled i. b6in DA metabolisn, with lhsl ot ct@aptne as a
Ererence atypical ompound The peterent at activdtion of DA etea$ and metabot6m i.
                          accunbens ar*                 b. ot pa.ticul.r Eld.n€ fq th€
amelioraring efled of nspeirdone on nega ve 'nighl
                                                symploms i. schtophrenia, ep€ciatty wh€n
aeciated with deFe$6n rl is impe€tire to inonilor for the meQenc6 ot EpS .nd TD an
i,1uG siudi€s, so that patents aG not disf,essed or ln@mbnabb, and to facitil.ia
ad he.ei ce wilh o ngoinc antip sychol c therapy n p.tients wlth sch izo ph en ia o I orher m aior




The althors wish lo thank Pakistan       sci6e   :oundatio. (PSF) and Univ€Env or Xaracni,
Pakistan fo. . .esarch g6nl

Authors' Statements

The   authofd€clar4.o conf    Lcl   of rnte€sl



The rBtLtulion.l and (inteonarionar guide ror rhe cac and       u*   or raboEtory aninats    }*
fo low€d Se the exoenme.ral oan for detaits
Ill          N:rs N, N.khaa r
       Kuok r,
       Neulo,hame|oqol*6d{ereE
       Pros A€in R.! 2003 r7, re2r2
       doir0 10r6/s007c6123(00)009102


       Pq 8Eh Ros.2003, 172 fi7-r.0.
       &ir0 10r6/s007$6123($)(ffi0
       h    ru df3 oi.ry'!€ mbsl1nk                 d,u! on   !dobe'$    dnd   .,osfrir9.    6Fhm3
       do, r 0 r 0r 6/s4079.3123 (o3)00e09.6

I4l    Prowsky     rs   coda 0c. Er pJ.     ve   o.ff Np. Munay RM, Kesin RW

       r2i .r3zr ...9r.    phoro1 em      slon @rp!.onr.d .J.ogophy srudy
       &lP'!hil||ly'19911&'5-26
       doirone,rjD.164.1 !6
l5l    sdid K, ranro9 LF, r4bsmd JA.
       erAsy.holt: d.{r ld 66r.€risod. schLoDhr.nD: :             MFdiE .did
       cNs Druoi 2009i 23: 337-355.
       doiro 216s/11311230400000mG00000
t3l    Morai.Gar* r. 6'.dy      c    shkP

       doiro r0164..u'on.uo        2006.10.c1o1

14     HenerP,        sdristu
                   Nor or CC,
       onarebda|9h.z-.danGpbanl{sm'
       Nedopsyd'ophahaco|o('9€7'17:.r-55
       do r0 r01ds0a$.133x(e7)mo02.x
t8t    Bruesemd      R.   w*c'hk     BH   rihmqmsw


       do,r0     1016.smr+299!(9rm?.x
lel    N@tun A, chzNr c,        v.rub L Miran rrJ
       NeumpMaob'y'1996:$1119-121'
       do   i0   r013,!o2e3em{er)00170{
l10l   NenerP, NomirosGG,        u   o M.   svensoi   rfl

       Prchopham.orosy {Bei) 1e!6: r2.r 7.-€6

111l s4mmsrj s. u.bqman            J.   tulacr s, Muii.     R. safieman a,   kne r, KEnic   M.   crry r
       Psrrhoplrma@bgy 1993              fi2(r   SuppD S35-S39.




                                            saPlM200'7l'xxl(-xxx.
       3|,?l!fd::l':,'$$:j!1**""hLophtmm6ch.i3holaciion]efiecyandlo|aab|Ity'

       Ih.   n6w .rypi@r anrpsychol          c    A rack   ol
       3rJP3y.hi.'y1994:j641411.3

tr.t x,!.u.)r vJn.or n
       paldc*tlh3d'izoFtnia
                                                                o'd6**ihh,bp€nrbdlwalFydddn4rh
       e'Jfuycrbw,sl:179:934
       do r0 r 92riD rx 6 503
                     r


lr5l   Nyb.ro s. F.rd. L.          E*si L. e

l1q    L.rcr'r s.        codA c.ad'erlJ       E
                                                       ron:1'o\ c.o'{ or4!       ro' sL1/ophG

       doi 10 r016/s014caD6r031617ex
1171   KasfS.n..43 .

       Plyohopiam@bgyl,,e]36367-373
       doi 10.1007/do2r30050s/3

nq Fr*tr Dr. B.rd F.6ar{r.
       .nd   s
             6B r.hrd b               'ldddJAf,.dbftrEgobn'n.nd&o.ren.i.!oh.
                                            r                        rs
                        '&d€niddtundtE
       M.a so Mdn. m01 3r aR354-aft6r


fq     8.bor     r       A[m.n s   8aemtu
                                                      dsr evtdeioo for     .ihan@d sdroneai. tundbn! toltdido
       J Cor Physidam sulo            Pak 20o9ir9:139-145

t20l M.ruorNY Masuba6s.Lderc
     cb$nerooor /p'd dndrro..                       r'p3rc-o - Jq!o.b.b..,ordopdmreo.               D,aro




       tui'rfi[c              drusr and   muoprsEry d'!hB         , ,ro   h r6td    ad muoborosy   or   !.iaophmt   .

       doir0 r0r6/s0006-32230r01267,7
lr2l w-.iee               ML,   xaF s. sdiGn a, JoB c. v..@im r.
       ootsinn.          D?   c6dor @tsnq pd
                                                 andRlF     dotu   i   c.ud.r6 aid Nld.ug A@6b.n3



I23l crfl      a.   Th..d@      a,   ens   P.   Mr3d€n cD
                                                     l..d@uqb.di,il'dunngmygHlob,l.


tzrl   8,9   nv vunlalqs.kbno                                                          MrRw pre.{yls.
                                                                                             ylypie|11'p.yc.d(
       d-9! lr23l€odefde!.o.endo "-€E01'oriso r.spE',dLoy.
       dor 10 1 1924i0 r 75 3 231

l25l   F.rde   L.   w.r.r     FA. Nord'rEm AL.   $dv.lr G
       Prydoph.@|@y1939:99:s2&s31'

lrBl F.de L. w6d FA, sbneEbndd s. B.rdin c, JordsM At- Ha H, s€d€lt G
     q doPrnine .ee9lc h eurer€prc,'r.i6 ..irepBlc p.d.tr. A p.,r6n mklbn
       rudy wih ll      r   q 6doe'ide                                                                 'onb!@ry
       A,d'GciP.ychiaty'1990:.721}219

Iz4 Ba$J c,A E".or{                   ,
       oe'n- srmbnlebolco@.'e@p'o,4@e3{roy.Ep.ddon..tr2r4-.pd.p,@


                                                                                            ydeL .olp.ychot 6?:     a
       AnJ\ydi,l-y2m1;153:360-369
       ddlo]j76/.p,iq,15€3.360


       P,a &ch R* 2m.r72:rz-197.
       dorr0 r016s0o79i123(s)1lm{
t30t   Narcam       s   Rec{ess cE, Baiow
                                                                                            poridoio   ..d   do:apine.
       sch zoohr R6! 2003, 105: 22+235
       dd 10 1016/lsoh'es 2003 07.005

       The errcd ol3€donag c agsfu on ha            op.ddo-    duoed     erarept
       Lire S.i r990i 47: 1609-1615
       do ro    10r   6o024.3205(90)90335.X

       Aptanlobgb|.phamadbic.nddink.|olcrldofli!'.lidore'aw{ljpsydF0c{E|
       Inr cr'd P.r{hophrna6 1995;r0: r93o.
       dol01o9z!@435c19e503mo-o0003
I33l   GoqosA         eoe.*' M BndmE!u*M
                                                    on or   .diprddh      dtu93:   Mpai$n   ot pt.pub. inhibition
                                                    lolhunli,h.m@|ogy
       Bchav Phahacor 2003 19,513-561
       do r 0 loszFaP 0b013.r2330cd322
F.l   s.n.d N, Baroor F. Hdm oJ.
      Neeh.nt€r ad b.h.!br.l dfd         or   84Hop^t tbrdrtio .'qo.e    to   E
      Prffior   R@. 2007:   ss 173-160

[35] Hara.      tu.d
              DJ,     N. Halm r\it
      Relsr    oi Mopendohddd r.d'E       v.oour ctrtulj9 ilomnl!       M   ep.G.n!@e
                                          b' burolEtr. in .d.
      Phama@r sioch.m Beh.v. 2(io7r 37: 11s-12i
      doir0.10164.lbb 2007 01 007
F6l   ArdeBon C. -ars ,v L!*JCP M.m.l R3 ,'.b.m.tr J,
      srddar w ui3 ch.ig* i b. nr fo towi^g tongr€m dmtntlf.ltoi   or   $piet     End   .iypt€
      NeurcpEohoDham.old€y. 2002: 27: r 43-3r
      doii 0 1016/sass11 33x(02)00237.7
liK:ityofhn.lMai|-r.:^Pl$9/{9

 '4)    ernoit                                      l|Ff    od turtur<bdadrd4b
 )::.dd..

Re: AP la39r09
rb{drlln     d-€/EEb




 @!d|oN!e&dsk'di|'.hz1oMc&




r//irilrFll6t !*rd{rJ!d:'d=dtr|&.yld?..5*'r&rai!t26tr@6]e
  Ilora rel.ted .ffcctr     ofcloapir..nd rieeridor.                         on   prtt.m of
 brrir rcgiorrl !.rotorb .nd dop.Eirc mchbolilm rld                                 on   tert!
                reht€d to Granpyr.mid3l functio$                          ir rrt!

FARIIAT BATOOLI'

AMBREEN HASNAT

MUIIAMMAD ABDUL IIIJJEMI

DARAKHSHAN JABEEN HALEEM'

' Ne,tucl*nlla? .td Aloch.nbal N.umphdMolog         Perch            Utbotubry,

D.Nd rett ef B bck nt4'r, Untur' t, ef Kddtu,   Iioe h i   -   75 2 70,   Petldal

'bp1*it    otEiotbdcd E   eiwhg"    Str$rd thiE tittoJEngh..ti's

o'd f..r@1o9,   Kadi Peaa




'Cor€po.d!tre;.tril b.blalol.du.k
       Thc prcsent srudy wca deigned                    10   .vduate th. behavioml aid .curcchdicol prfilcs

oa cl@pino      ed      risFridone in ms in                    .    dosn.p..dent          nun.i       A.imrh ini*!.n
 inhpsibBlly                      clMpic                                              r
                     (i.p.) whh                     (2.5, 5.0       dd   I0,0 me mt       ks,')   d rk!.dd@ (l.0,      2.5

ud             | *d wifrc.d I h ld ro 6lk . bEin $pt i Hypd@dw
     5.o mS mrr kS

cdeB Omc c.g. &rivity and €6lepsy) w 3u6it.ly noniroR/ in cEi !trinal rft..

Ilc dnB or idlin.      ddmiDistalion. Borh druBr sig.ilicandy (?<0.01) deMsed loomoror

elivity only   ar hiSi do$s and          lll   rhc      d.or@s aE in dN               dep€ndsnr      me..r, Muimum
(r00 %) erircpric porcnri.i achic4d onty                            d   hish do$ (50 ms            rs)   oa.isll    idoDc.

N.urocllmi6l Brih{ions             wc ffjcd d ty hieh !.'foD{€                                    tiquid chmrbgnphy

*iin ekdloh.di4l rilicdi@ (H?LC-IC), B.th drgs d aI doss tignifidrly                                             {p<0-0r)

increacd rhe conc.ntdtion drhomove'llic .oid (HVA), r melabolit oldop.nine (DA), in

$e sl]idun, Dihydrciyphoybetic &id (DOPAC) l.vcls iroaa!.d in tn.                                            stlitu   md

daRaed in      thc   rci   of b6in panicul.nt                ii clozpinc-i.jercd 66.              5-Hyd6xyindok&€tic

&id (5-HIAA),    rhc   padonimr nabolitc of @tonin sqnifidly                                      (p<O-01)   dcard       in

rhc sdiaM.5-HT (r.h)doxya)?taminc)                                  w6 sknir,kdy             @<0.01)        ii@.!.n    by

 speridone and   daEdcd           by   cloapin. in            thc   F$   oa   b6in. siriahl trtllophan (TRP)          vA
sicnif'@dy (p<0.01) dccffi.d by rftpqidon ed                              jrcE.d       in En of bmin, Thc stiat l

lwa/DA djo incrc.s.d ard 5-HT tonoE nr. EMhed whagcd in                                               drc   a!   of brain.
'nrc tudinci frod rh. snrdy suag6t                  !   po$ibL rh.nFric            atpMh fd           rrsring    cth't
schiaphEnic parianr5 $d        m       lhus    b.   q   B6:l pElictiv.         tool in di.   ,@liiidl        d,tEloDn.




K.rryordt: ayDic.i                dE.ics, dopejr. Dr Eep.orl,                         .ftpymid.l             3i& .ffers,
                        'liF
sr!{oninu @Dtou, 5.}i4phEnia
                        M. of rh. n6r $v.E md dcbitibrirg nqjor psychhric ds@s.
               Schi&phr.nia k

     Thc i.toducrion of mriptlh.rie drugs wa3 indispubhry o
                                                             lEd advane ii rh.
     pnamelh0Ep, of nmtd dierd.F 0). Trpi.d tud !t
                                                         liqt i.@t.prics hive bc4
     ditre. .r.d on ttc b{sis offi.n lbitiry b.iltue dolarr* (DA) ftt.e in diff.Err
     n.*crmph.lic DA p6j{tjoc,                             A.y?ioliry         h$ ben enb.d ro tuni,                        {j_
     nydrcxtlpt.min.; t-H1l md DA (5.Krr'                           D,     htagorhm rh( D.y b. invotwd witn                rho
     anriFychorio    .fecr    (2).   a   majority of      $     zophEnic      pdie,lj rc+ond   !o   cl0$ic,t ndmteplic
     druts shicn !rc b.ticv.d lo acr hB.ty via bl@trdc ordopaniic (OA)                          q EaDb6            in timbic
 ocoB (3). Motuv.i n\. .l)n@ibt blat d. orDr ,Epro6 in thc b&l so3ti, h.s
 ben Mi.lcd wirh aDp.enE of qrarr@idat sid. eftats (EpS) (2,
                                                             3). Th. D?i€l
 cr.ct of ad6inincine            a    DA @Dror {r.gonisr is a eppEsjon ofsponbr6us hcomoror

 beharior      lid   clioibrion ot       i   sktc known         d   crht.psy (4). Sclcotivc    ot    gonisls     ot DA-D,
 l@Db^          m    .licil @dep6y           (3, 4).   Mo@q, E4caios             on rtE   sri.rM .!!qr           ro prry   e
 jnpodar El. in rh. .t;cibrio ofqrrlcA, (a),
                                                                       rn    dop.biE    s'!h   hs o.ditioElty h@
 co6id@d         fudo.nbt               &ri 9 (5). Wirh Esp€r
                                     ro rhe   6nr.ol olndor                                          ro   rh.    d.bDi4l
 sire of acrion . vi* hs da.top.d thd rt n {um k invorv.d

*tapyreidal           moro!    tunclim.        An.eidton                 of cliniQl titcnluE siow dat halopridol
js w.y    lit.ly b p6d@                       d@pirc
                                     EPS,                  is   El.rikty untikcly dd ,ijFrido,.             is   $dcyh,r
mild in    h3        of th. pbddion            tle cfrd             (6).   I. cmp6d$n *jth     ct   $i6t    n.uDteptics
ag?isl anripsychoic           dDgs such         s   for   .Mpl.        ctoarine ed rispoidon. hlve ben foud
to   pos       rmpovcd     .ftdcy agajN eg|tiv. synprmclolqy                          ,nd oou* . rcduced incidercc

of EPS    i.   clini@tty   .f|6riv. rtrss        (5,   6) Tho pm.nr           wod<   ws und.tukcn ii a, a{spr b
s.in ftldEr imidb            i,b      rhe    Der,,ift           of &rion of     lDliot &tjprrrlolic         dtuss    s!
dar*.r wirh low pFFDsiy for irducins EpS in nrr
            ClozQinc. tn. fiEt ofrh.           !t!ic.t {riFr.hort, hs        ben    FFi.d       ro b.   lfdiE in
     appro$mtury           on   lhird o, rwo     lhid of pdi.nr      widr   kmi!          Er3i!!t       djse (4,
     Obviousl,    a   gel    of curcnr   i.uDt.prjc Es.Eh h lo d.vetop dtipsrhorje shpounds                    yi$
     low inciderc? ofEPS and llBnulocyosis, Orc oflh. appl@h6                      ii   rhjs   co   dhs    b€n      b
     d.6h.       n u@h.hictt/ ph@eologol                     cml.r.s of d@pic $d ot,6 .r?ic.i
 n.urcr.p6cs. a tublc fatoE of $c Dh!rulos| of ctozpin. i, i6 !fiiniry for
 s.6ron !8ic t4pr6 r.di.utoty 5_HTa,   bd t-ttTr^ Eepiots (s), Rispsidone, !
                                                         '_HTE
 beDzrexel d.rivativc!              provided   tudhq.videne       rhat   poiflr 5HT:^ lnLgoniso .onbi@d
 *irh milder D: .n6go.isn (9) cuh.d in signjficdrt impEved ctiniet prcpcni* (lO).
 l.d€4 b .ddirid             to   src6tu1    d.d'.d
                                             lsiliE 5rDpbmi rGp.ridonc nllcdty
                                                         of rh.
 imp@rcd rh. icldjt. rynphs of el,izoDhMir wjrh . Io* tilbiliry
                                                                 of Eps Q, 3. I ).                              I


 Ottur aurhoG have frlon.d d.f ing r dliprrhoric 6 a.y"i6t bascd on ctiiical
                                                                             .mcrcy
 Md a roa pbpensity lo indwe Eps witn shonncfr                      lrcee      od       no indkri@ ofGrdive
 dyskin.sir anq bne             l.m rEadE t (r2).
           Thc   prim., objcriw of rh. pllsr $dy w.r tnad@,                      io @m!€E           d. .tr4$ of
 vdios dos            of   cl@lin      md rispeidom     oi drnpymidatmobr               tunctions and on bnin

e.tororin md DA ncrlboliM, Homov.nillio lcjd (HVA) ond dihydroxyphcnyt a@ric acid

(DOPAC)      @ d. prcdohinmr hcbh.til4 of DA, whit.5.hrdbxyindol.                               !di.     eid   (5-
HIAA) G lnc pEdomaer h&botii. of J,!tr. Th.cfo,!, in rhe                           ptgr        sudy     .ft.s of
cl@lttu ad risp.ridorc             e    .t$ @nl!6r.d    on   SVA/DA ad 5_HlA /5_HT 6rjos,


                                            E)(PERIMENTAL



     Tb.   pDr6l       fo.   dp.rimddid h !pp6r.d ud p.rfm.d                    in   $id.eddoE             with
ln    Cuide for   lh.      Ce sd        Us. of   t   bodory   A.iMk       (Gtitorc of bboElory Anin.t
 R.sows on Lif.            Sci.nces, US N.lionrt             Rotuh Coucil,                     t996) dnd th. lnsilurionrl
 Animal Ethics Connittec (IAEC| Univouity of K.@hi, P!knbi). The euid.lin.s of IAEC,

 rhc   Sorcning bddy fo. oniDol cxtcrih.ntrrioB in Pdkisrdn,                          w.r          nrictty sdh.Ed ro du ng

$c *hole uinal exp€rimdbtion pDreol Loott]                                   brcd   nit.       albino-Wiia. mts wirh          4
rvcdgc rcight of 130120 g, (n!4 aah! Khd univ.6iry, Prkish)                                          w     f.d srdd.d di.(

.rd .llo*rd wrE ad lt             tu.    It'c eimG            ye     gMphded (M n6 !.r €s.) in &
cnvircnmcnrilly @itollcd           mm (dblarr r.mpduE 2412.c lnd Eldiv. haiditt                                             5J1J
yo) on   !    l2:12 h lidt? dd. ctllc (ligh6 oi ar 7:00 a.m.). A                    5i.y @lirriario.               paiod     w6
allar.d b.roE einals w.E u&d in .xp.rincnl!, ARq rhis p€rio4 ad 24 h h.foE fic

beh.viodlksts, ih.aninals w.rc individu.lly hou$d ir m envnonmcnElly conrollcd tcn

@s       in   lBnepenr P.Epcx oalca           (dii.cio6           26x26x26      cn)       in   d    order io avoid     ey fale




          ClMpirc      (SiF. Gouy) q6 dislvd                            in   . nhtnm volm.                 of 0.1 mol. L-t

a@rjc .cid      dd tH adj6cd         ro 6.5       bt MOH rnd dilucd *t.h pfiFiolosiol slirc {O9l.
Nacr) to d6i€d        €ffirErioB                 ud lO.ODs'lrmd injdd in volumBof l.O
                                         of2.5,5.0

sl   k   r hody   ftisl    . Rispdftlorc    (rNrL Us) y6 dnsftn in O.a mot !r tari.ri. @id
dd     pH .djuscd ro 65 by       N.oB &d dilur.d *irh sline b ih. d.siftd cdentr ti6r ot                                     L0,

2.5 and 5.0 mg       nll   and   injelcd ir volumos of             LO   nl     kr    body wDisnt, conrol animolJ

rc@ircd equl       volrn. oav.hiclc (O.l holc ! r r@tio !cid,                       O.l   nol. Lr N'OH !nd/             or   O.4


mol.     u tuic        eid dd slin.         in rhc Etio of          l: l:     8).   Irt    rinals       sd    injct d ii.
b8|(ccd d6kr         hets$       10:00   ed   t   l:00   h   sd   rh. rcuE of       ldminiMid              rscd for rchicl.

od dngt       E    iitrp€riiodal (tr). Mord &tility r@iioEd fd                             tO   nin shjng      |   0   nh   dncr

irjatjod C&l.psy .trels            of .h.   do$      w sEd              f.r r clt off ri6.            of 3 min     sdirS l0
      h'n pon injcctid! ed sihab                      *w     ki    cd   b @lld bnin      $p|c      I   h   lno lij..rioN, AI
      hc EScnl! uld du,in8 dody w@                      of.i.lyrjql !nd.,


      Dos.-r.latat motot .lIets ol.!o.a,pt                              .   or.r rbD.,Uon
             MoioFEt.r.d .ltars of                  $. dna! lrw nonillEd             in p.rslEr   *rjvjty         os6     AniD.lr
      *.ru @dimd jn pcEpc, .crjvity .!Ce *irh                                  iw dd      @EEd         fls        l5 mii    b.f*
      injering rh.     etift     or d03. ExD.rjftcd wE c.dwtcd in                         . $p.*           quiq fum, Mdd
  d'rity h        dc   divirt             *s Mirdld uda *tiE                             c ,6b.r
                                   box                                           li8tr                 of c.a.     tuini! !ff
  l0hhtuiis             I   cnin F!. ntdioc                 (t   !).
  Dos.-.dat d@trt                 pd..tt         ct,   of.lozrzt            .oddq.ruoa.
  c.il+r,            ralpre ed Grd ion oa alml ,osu,r, 6 oaluld by
                  d.amd      s    thc

 na6 ol . b6r B. B& ld d.l?DiidioB l@ qid oot by garty E@ing
                                                             nrs doh
 0!cn    hoG 6s6 &d pt&ing                    rhai.   f@r.s @ . hdidnl b!, fu.d .r r tdghr of                              I O   M
 with lEads       ofuiroh         upMds        d      D imhld           ede     ,l d eirc   0160"      *idi d. hi.d tinb6
 .!d!cr.d (14). Tn. bn8$ ol rim .ruins rvhic!                                  i& Dinrt G6ird              rhi3   B,irid E
 .tcdd.d b,IBuiig rh. rift 6!h ln. de@t of rh. nr ud Moht of @ of its
fo,ro.*s. Ar uiut lo b. 6r.d G pt*.d d o inclin r $.r& (26
                                                           x {O cn 600
incliMrioo)       td clr.ttlim.           3   Dir   (tEO 3). A         616r d ch.rs6       a6   Fjjria inn          da.ct,       d
dE     irliMrio( Tin.            (in s)   s    drus    d stirc irj.s.d uimts ,wrc                          inmobirc     d    .h.
itr   rjdid E moirdld.               Anituh           not   mvinSo lh. imti..d $.f@               up ro     ! nh wE         lBr
b..t    in th.n   696.    DdN dr d|.'s, (.rcidiig ad$ Buns) tn. din t. lw
                            To   b.nd
r.ecrl twie .t 4h rirc i .mt rd ont, tn
                                        s,.!ra duE.nD ot fim. vG E@i.d, Tb.
      !@ vs stold.d s lr,i.nc, otmoMdr
C.[l.pfic                                                                        Gy cul.ottrin. (t So O]           tOO,

N.atuchdi.d analrtls
            sarina,   croapirc or   .irFddo. iij.crd Mimd,        rR      tdtt.d I           i Dd injdrim. n ,
   dis*rio. prcduE ws .snti.lty              r4. s   dsdb.d .ts*l&E             (   r   5.   16).   A fEsh bai,    w8
   dipped in icc{old      eue     Md phc.d wirh irs v.nht   td.     up   i.   rhc motd.d            ovi, ofr b6jr
   srier, Fin ffshin!      tind   wiE,6 ir$n.d   into rh. doc   ofrhc,rc.r               ro grv. stic.s     of2 sm
            Thc slicc conbtnin! $d !m wos rcislbft.l ro
   'icknc$.                                             i ddc kcpr on ic.. punches of 2.J
  mn d€neh wcE frad. bita&r. y in lh. ndliua ro co|cd
                                                           rhc br.in region. Th. sriarum
  arsobown6slrjaEbodyircosfi.r@or3ri.nucl.uiis0su!..niat(i...,i,sidc,Flhq
  the   on rhe ou6idc) pan        of$c rtd4phlton/.crcbnn. tr        is   rh. nalor inpur surion of dr.
  baal eeslia sysrcd. rn prim(.s (includi,s hu!Mr),
                                                    lho sri.tum is divided by a whit
  rotur r@r allcd ihc inrcm.t qp$L              i o oo sbh eld                  dc.tudab wtes                     ond
 /ur@.n. RAt of rh. b6i. w6            rls ddd   fo, rhc bio3ojc mine                          Tte    spl6 w
                                                                                    'ey.
  stoEd at -70 .C for dlc          c*inrio   of DOPAC, DA, HVA, J-HLAA                        ad      5-ET by iigh
 p6rM!@         tiquid   cliM.ioenphy *iin .|ouEhoniol d.Erioi                  (HpLc_EC) O 7, t8).




           Bi%dic     ein6    md   lh.r tujo n nbotird *w.sser.d wirh                        l5O    d orpenhloric
 &id lHclo.;     70 %)    f6m bain     lis   puct6    (< 250 llg)   cnl! ,          ,mp,c           oc&p tuptc
 p@!@nd ndhod (t9). A J              !r   (p.nictc sie) ODS   6tmn            (4.0      M      i.d.   od   250   no
 rens.h)   *6   us.d, Mobilc       pne @np.is!    of h.it&or (cHJoE                     r{    %),     eryt edim
sulphat rc.m3     70)    dd   EDTA (o,oo35 %) in o,r sot L.' phcphsrc buffd orpH 2.9                             ps
ped     thm$n thc column d co6t&r            trow .   0,o nt hin. ) *nh tn hetpofwaren5lO
HPLC punp        (w.re^ Corporrjon, US), El*roohcnicrt ddenon
Schinada LEC 6/1 dcieror (Shihldzu ComoEiion, Japan)                dr   !n openhn8 por.ntiat of                 O.s

V. Tr,"rophd     *4      debDinod in   ! !.parro ru, .r M op.htin3        poEniirt of LO               v (tZ-t9).
The pEscnt nelhod .mptoy.d ro study thc cdoet! of inr.pentonqaj
                                                                idm,nifrlion ot
cloapjnc &d isp.iidonc @ biogcnic .mjnc! in ! nunber ofdi$relo Er bain
                                                                       ESio6,
            Att bcbvi@l ud                 Mt!.h.oidl p.fu.L8 r@ {tc!t.r.d fd ah uinul. d rtE
   d.[ w Fes                   cd     5    &iihm..ic me I tud.ld d.vi!trol si.risri..l ,..ly5is
                                                                                                s
  p.rfoorcd cing           o.-hy           ANOVA     (Mtri, oavei|e) !d rbr,/e @p.in hs                                  do..
  by Ih.    Ntu{ak                    16r.

                                             RESULTS AND DISCUSSION

            Th. E$lls or rhc .xp..ih..a                    .hiniry      rh.   do4rt        ed lF.cts of cto4pim          ud
  ritpcidon.     d     b.h.vimt d.ficjr!             e     lhoui in FiSUE L As              sn     an    FiguE t, ANOVA
  shoucd    iigdfi@r.lldr ofct@piE                         (2,5, 5,0   &d   tOO    nS tg-r).nd risFnddE O.q 2.5
                      r)
 ed     5.0 ms   rs        d   6010.       divity   (p@,0 D &d         d od.pay          (pq,ol   ).   o[   d.|! stFecd th.r
 .ll   ilr.l@        ofcloapirc &d risFriddE                  l@       toqd   ro   d.crc      no@ 4t!ri.y in.          doc
 @D6d.nr         fttud         (Fi& D. Borh dturs             wf       tbud ctr.t.ForBic oty !r hisn                   dos
 How6, h}'olodoiE ctta6                             of bod drues        tw EoiH              .qurvl|.d in tn.         DNt
 nudr,   talrd        &at'si3 sholr! rt.r                6uins     OOO %)     qrd.p, eu.rd                  onty   d r d@ of
 10.0   hS *Sr.toz.pinc dd 5.0 nS *8' otdFridorc
                                       *tB mpFd *ith rh.n Esp.dirc
 srjm-rsrd ni. Ctdla* did nol &cd* tamer divir, d . d@ of 2,, m! ks.l
 shi.h ir   t|| dos idpdr                  nndins of tl,.   Dled       snldr, No    @t.rsy        s      ob*ftd d dos
of 2,5   r! tt   r
                     od    5,0   ns k8       |
                                                 cluthe Alici,          ud 62r{     dlcp!,        w6 p,lducd oly .r
otl.Dloldic d@ ol       rt Ei of.t@pina
                                 t   0,0

          hljm fuding of lnc ptqr tud, i! lh, -urc .dninasr..tid of ril6idoE
       ^
Elrircly lniaomty inc|lq DA El* ud haddj$ b d. sr,idum Egion of 6t bEin.
Th. popos.d raheiu of HVA ch..C€ irvotB cuc bt@t!d. of pE
                                                               ud lcrsyryrjc
D EAo6           (3, 20). T1'. pqry..pric                btetld.   incB,           rhc   uolnr         of D^ ct.scd     o
subs.qqr &rjoi pot trli.l: blr be!@ Dr ,osryE                                     !er6u e
                                                                            ric                        ||!o bto.*c4   *@
DA   frtMjsjd         is   dEnlird (ro).            ln   ddilim, i! i3 p.$ibt.lhd o. a|lrirc t&k of                    Eps
:.




     J




     !*
      t-
      l-


      t-                  l6

                          I,




           tue.,|4,re.!|fr!.r$r.6k)

                           i.
                           ;r
                           t.



:."
                           tr
     nolq cn*ts *ith cl@pin md risp.ridom idniniturion h                                 thc D6smr srudy @utd b.

     ELaled r0   so-lay inr.Eolion b*wcn                 DA Md s.HT         ccrrou. Figur        2 sho{s rhc   clre6 of
     vdioB dos! of oloapire dd dsp.ridoc or lhc l.wts of dopdin (DA). m.bbolib
 dihldrqrph..yl.erjc                  cid        (DopAC)       .d honotuilic &id (HvA). md                               5-
 hrddxlindolaorjc rcid {5,H|AA) in rfi. slrioom. ANOVA sh6s.d                                    silrintutdrd of
 .ldjpin         on rh. lcv.ls or DA (p<0.01),                Hv^     (r'<0.01), DopAc (r,<.Oj) .nd             rHIAA
 0<0.05),        Ef6$ or rispsido. krc                       rlso sisnifi@nt lor HvA (z<,05). Eftacb                  oa

 risperidorc      n   DA (P0,05), mPAC (p>0.05) od 5-HjAA (p>0.0t) wcE not sisnifi@r

 ComDldoi wnh Po*r-c                       diltrir !ho*d.trers            ofn5Fidonc on DOPAC cheg6                  w
 not    signitrst wh.r @oFtld wilh Gpcritc @@h R.s irjEr..t wirh 2.5                                     ms    t(s' rnd
 5.0    n8   kli   .xnibird pmoDo.d 2-3 lold incttas in HvA oon€nrErion ed des.
 inoEG wcrc.ho                compdabL when             nGrEd.S!i6r 3.lin.-fticd.nim!k.                  HVA lev.ts

 wd.ho imF8d                  fou@ing        do.dmiiiit        tion of cloapine      ud rhl in@.rs tBimM al
a    doe of 5.0 mg *8'r-           MqinM incl*!              of AVA   *F       gutcr ir dsp.ridon rrr& ct@pim
inj@Gd       &iMk,It         jr   nd gm.nlyagE d rld cliniol6po@                        !o   trcuDl.Fi6 ir   Miared
vidr    & incEs      dqf.rion (21) rnd rhe ob*nd ircsss ot HVA pdiculaty
                        in HVA

in th. $i.nh Gig, 2) ffi bk n c dininguish.d ctini€t fatoEs ot borh drugs in rh.

ft.mcni of          psyohosis.        Th. @rc.tu tion of              DOPAC         al$ incl*d        lottowing th.

adninisrrdio of cloapin d i d@ 012.5 nla                              r
                                                                 kg       ed   5.0 mg   tqr. DOP     C toEls did     rct
itl.lle a qbl.Dbsoic dE                          of   l0.O   ng *gr of clozrim. 5-HIAA l.Els incEEd
foUovin8 dE .dninistuion                     of high doe of ris,€ridde bur rhe                       irc|@ w
insignifio! ConvcMly, cl@pinc admintrdi@                              did   d@e         5-HIAA conMrdion            6ly
ai   hid doe oi       I0,0   ns ks    r.
                                           Th.   d..Es       rnioh wrc not sisnific.nt by cl@piie              at   d@s

of 2.t ng     krdd           5.0   ng ks'r   **       3iSrili{nr (/<O.Ol)      ar   ilc caol.pio8onic doeotlO.O
         DaE   dDzd      by ANOVA      d   dE   t4t5   of DopAC. DA, HvA! 5-HIAA              od 5-rf[       in
 rh. En of.h. bnin iUushrd in fig!re 3 ,iow.d signifitui .rI@r of ctMpinc on DopAc

 o<0.0D, DA (,<0,01), HvA (2<0.0t ), 5JlT (2<o.o r ) and 5_HIAA (?<O.Or) eic.nhraons.

 Eff.cts of.hp.ridonc w.rc ont sisnifi@nr for HvA (p<.ol),5-H|AA (,<O_Ol) md 5-HT

 o<.0r) qd      not sisdfianr     fd oopAc ud          DA {p0,05).      pd,r& dpsim                 do@ by

 Ncm-K.uG          B   shosd rhd rispcddo* sig.ifi4dv in@ed t.Ets of liVA in .                        dF
 dcpcnddt     nor.r dd all lhc incws wE                   compdabl€     rha D6ufrd          agair$ .n?ir
 Gpetive slin .lrcatcd sDlp of nr. Cov.B.ly, cl@pine onty                     at   ! dos   oa 2,5   ns   k    l

 sigiarotly dcoEacd HVA cdenf|tim,                   In del!.s *rc            nor signitidnr    d hider
dc     of clMpirc (5.0 r|d          10.0 Bg kg-).     c.Mnhtid of Dopac lho d,r€$d
 aollovhs ln. odhinisu.Iid or cloapim              d dos oa 2.5 rd 5,0 ns ksr bur nor ar th.
ablcrbg.nic d6c oa         10,0   og |(3r. Th. @ic.nrdrion           oa 5-HIAA      rnd 5-HT incE6od
lollowing the.dmirkhrion      ofrisp.idon rtdor6of|.0dd5.0                  mC kg r bur not at      dos oa

                           d6 sisifierly d6@s.d th. t.Eb ofJ.HtAA h rh.
2.J mg kg-r- Cl@Dh. ar arl dF

sdntun dd B ofrh. b6in. 5-HT lals w .l$ rLcE scd sig.ilisrly.r d6g of2.5

ed   r0.o me *s-r in   rc$olrho   brain (Fis.3).

       Serctone4ic msohani$s         e   ale *noli to          inlluence neurclepric-indu@d    ohleps)
(21, 22)-   Irt. sdotu4jc .f.cis ofcloapir. lko h.w bd.mphGiz.d e po$ibly                            b€ing

rcLtcd lo    rh. iqe clinidl cheotcrktiB             ol cloz"pin. (22, 2l), .nd @ndy n w6

$egd.d thd dc t-HTa/ D            birding Erio @!ld b. u$n b disr:nguish            b.twei rypir.t dd
.t}?i6l dipsyciorica A dace ir           5-HT mct bolilm by         cldpine   is   cxpliqblc in tems     ol
drugs Foderalc affinity lor 5-HTjA    rcc.pb6. Tt!u. n.isuEhenrs of cgionol OA                 and   5-trT

htubolis      in rh. Rl br.in hive indi6r.d         $.t   riltcridon.   .lle*      DA runov.r in     6orh

n@lihbic ed nigenti.d r@in I FgioB ud,                    to   em.   .G! lls        5-tll mdlnofis       jt
rh.$ dg.r    al*   (21-25). Th.   dcEl{ld       qfccs of clozpin        fld ns!.ridoic     @ rh. Ly.ls


                                                                                                         IO
   of rryproph.n md Oc               db     ot HV]{/ DA ed 5-HtA4,/ 5_m ib lh. d.i4un
                                                                                      ud En                               of6.
   bEin w.c d.pic&d in               figlE    4.   ANOVA    Frfm.d 6           slrid,j d.d $o*qt 5igiifiMl                 .Fdl
   of ri.pcddoi. on           'Ilp      (t <0,05)   dd i6i3nifi{t         for HvA/ DA (pO,O5) dtio. Efi..G                       of
  croapiiq w.rc iBi8nilim! ro! rRp (rDo,oj) .nd
                                                sis 6c,m ror HVA/DA (,<0.05). Dab or
  e$ of fho brdn sho*ed iNigrificdr cifst of risperidone on TRp              pos"r@                    lp>O,OS),
  .narFis shos€d            dd   tl'e   dilr tVA/           nio   dd6.d
                                                       DA                      in dE      ojabo      of   ct@pin. inj€r.d
  ,!a *h4 @6ped wilh                     sliFrq&c nr od             d,o   de@             no.   si$ifi4t i d66            of 2.J
  {d   LO nA      ks r      *.8 sisnifidr !r rhc do-          oa to.o     ns   Ir,. conwely.h.                 j-HT hmowr
  @ '@m.d unatr€Ed fo Ni.g                              tnc rdniiifrrion of              d@piE Adninishrion of
  ftp.ridon. iiSnificaitty itu@s.d rrvA/DA Erio,r hw doc (1.0
                                                                   ng [gr). ANOVA
  p.l|om.d on th. d'r of rest ofthc br.in show.d insiSnif@l
                                                            crf*r of cl@piG on TRp
 and   t.HIA,      J,IIT ctio. Etreots of rilreidon.                wft    ako idsi8nific.nr for TFJ, and tor 5-
 HIM/ 5-ItI raid. ?o*r@ lcs                         showcd rcn_stsniriocnt         d6t&          in bEin S_HIAA/'HT
 hrto followi.g irE admirisb.lion ofcloapirc od rispsid@
                                                         6                                  snpofd        ro   etii+rd.d
 dE,   ii   .h. pEmt sludt               a itlo@        in br.ii t.v.b of 5-HIAA            @!zd oty rt ldv               (t.0
 n8&) .rd         hi8       do$ (5.0 msAO of tupcndon.. rD                     cdh,             cr@p,rc adniillbdim
                        '
 dcmEcd              tuhov.r. Tfi.          d@.s wd           noF mek          d   ii   lhe rcn ol   &. bnin ths     in    th.
             '-LIT
srrialun (Fig, 4).       ou r6ulr5         susgca?d rhd     tn    cohpaison oflfic.ff.cls ofrhcE two dru83
sh.wr lhd     4    incre@ in Irya con@nlrtli.n in Ih. $ia1um dd                              delle         in 5.HT   i[    tne
en or$. bEir         may b€      Eko s        a    n uehcEic.l pbfiG or.r}?ial cl@pin+tit , mliviry.

                                                       CONCLUSIONS
        In   ecl6iol|         the    pEer sdy shM                rhd bodr cl@ritu            od,isFrjd6. i,:c'!e
brain ESioDrl DA            tunoE. in. emFnbt mune, rh.                            pErr      resul! abo susScs rh.r
adhinisration of aDlicat eripsFhorios at to* dosos prducc fcw.r
                                                                BpS jn                                     rehi of tc$
hlpoloFnorive        .ff*ls jn 66 in b.tn fDitiu                    and    no!.I .nvircimcn.s, Ttk                oi      b.
 qphiMbb B                    ln{
                      d.ra3         r.nd   &hnt sdojn leD{G
                                                    e t'w, & irrclw in ts a &v
                                  llnl8, q ,_1II n.rrtoti$ ft q&nftirivdy
 EPS Flduoaon. Tn .fitcrs of hodr
                                                                          3initu_
 Sdn druli dat4 tnh 5.HT nd.boti,,
                                          in bnin &i.tun. A|tnd8h oda .ryDic.l
 r@r.pr* @td prode djlr@ ,.u6lF.ic.t
                                       cfers dlp.ehS upoi th.t &dviry
 ionl& dif.tur o?< of DA &d ct!.onin @F.q
                                           & iE@ in DA : s.onii
 mdboliE dio Fnitutrt, in 6. ,ei.nn my
                                          b. LLn G                                  . Dudtaidt @fl.               of
 .ryDicd, clE rirllit sdvn . Tle
                                 @l|! lhafoE              ol,-m i.     &ss.n & inpdr&r ob
hlnar Eir.r. *ni4phei. &d loc i,rctqE of
                                         EpS, Flrc so,t *iI idad,
6.na tahas tr ine .rnprdtr!'
                             s E c es DqF'lhdd !s6E                                            tur   do   d 6e
ES.

ActnopL.ltm.n.'.
                              -       wld tit !o rh,rt p.ti,!,
                                    7rE .urh@

eSFrSi<Ur'Ch.n          (3it8).d U!i6i9 ot l'Ehi Atr..ru
                                                           for



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       do!.'rho{ic dE!', ta.t, p,rk&, lo (2005)
                                                    ,9_t04i DOI:
       IO   l03vsj,nr400 tJj6,

 2. S N.r6.4 c. E Retk                     s, K. S.   Ados, ,. N Nob!8, .trd                yqor, Ani.{tBit
                                                                                      S,
      thc !qDic.t.       lt?iar &nFrrholic.".ffF,n6                    !o   t.kfdidol d.ldidoF !:d
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      r@in     .nd L, S. pitoesry, In vih             eqp.rc, ofdt.$t ed Enpo..l               conj..t D/   !\
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 4    s. l€uchq C. Core, D. Alblcn R,R, Eng.l, c_ Li                                        {d    _r.   M. D,vis, S.@d_

      Sddtion        t6c fiBl{ddtid                         .ntipryctdic drugs           fd jSi4phMjr I                  ncra-
      D.lysis'    l@,,       37J (2009)       3   t   -41i DOt: t0.l0            r6/SOt4o5B(03)51?6+x.

      M. L. vaddb.r& S.          (.pu,                .   Solina       C,    Jm6 .nd    F_   V:@i.q Do!€niB D
      |@ptor GcuFncy pEdicE qr.lcpsy &d rlE suDpKion of @ndition d                                                    lwit rc
      Epon*        b€havior      in tut, Pt.hophmtotopl,                               150 (2000) 422-429; DOI:



      J. T.   TEvifl, M. Lyo$,      J,     Abhe4             D.   C.rio6, M.        Finn ind J. D.           S!tdo.., EfiaB
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      eMDymidd hobr ntaion, Psr.h.phtn@olos. t32                                                   (1c97) 74-3li DOri



7. S. ritur tud P Sema DG                                 6j djsidid tu'                    dE doponinc D: @p!or
     dpl,i'     dE erion      ofllrricd           dri!6tchorics?: A n.y               hnorhsi\           rz I     pgrr,tdrr,

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3.   A.   N.mta      C.   Cl'.pul   !. v.nicl. ad                 M.   ,. Millnl Cl@pirc k               a   paniil rg.ri3r   .r
     cloned    bM     solonir 5-HTl^                   d./o$           N.umphffi@L.A4 3t                     11996\   tt9-t21,
     DOr 10.r0r64028.3m8(95)00t70.0.

9,   S.   Szymoski, J. Lieb.mai,             S.   Poll&I, R, Munn., A. Saffemin,                        J.   Kin., M. KDnig

     od l        coop.,, lh. dopMrn.-ffibnir Eldidship.n (loapin. E;poM.
     Pst\:toph@los/, rr2 (t9tt)                           S8t,S8* DOI I0,I0078F0224t01 L

lO. M.    Cupb.ll,   P. I.   You!3, D N. 8.t                tu, I           M.   Soili ud   S-   rl Th.mli Tt. @ of
     att?i€l    diAttnoi* ir dl. @e.Mt                                 of   r.!'iailEail     BL J. Clia Phaneol,

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                                                                                                                              I]
  I   l. R, Kutu, G, pdiq ud E. N. Dh.wo,                            Cffip.diE b.h.tiod .ff4l, orrpic.l &d
           .rypi..r oritcrlhoric dtusr h                     ltss    6tt y. Ev. J ptw@ol. 4, (i@3\ rj3-
           r3r;       rot:   t0.t0t5/so0l4-2999(02)O29r7{.

  12,R, A.              Br6!.t! K. &l&dsc                    tt M.jo*.,      R. S. Mu             itltl p ,. E                md   I_. S.
          Pilo,slq, ClFani.ins linbic              sk riE D,Dr Glpd @upuq by ,ispqidd.: r
          Ir8rl{pi'lcFi.r.               SPET   iud, I Ctia ?,jf,h.phq@t. 2J (2003) ,-trti DOt:
          I 0.1   09?400047 t,t-20Gm000-O0OO2.

  ll.     D. J.       ll.lcD,   F. A.!oot, N.     ll   t(hs,    N.   rei!    O Ati Z         S.   S.i8      lld    M. A,      t.la
          Dif.Ms i. d. .ft.$                                    d D.an sronin dd
                                                  of n bp.nib ..d chdpiF
          dolqniE         D.lrlolifl &d d !.a Eh.d !o ofrprmid.t fsritu in nrs..r/.d
          S.i l/o"tr         E (21,02)   BRIJ4-BRJ6 t.

 la. F,      E.r&r, S AnD.!.d D, ,. tLL.d! Diry $!?t@dr.liN of uilo .i&
        .vid.@ fd s .Bn !dd.8ic frdiG fo dins hrlop?idot wirt (|rtnt In d
        n.dirl pEilor.l ee4 J col pb,i,rm.r,; ror I (zo,r) ,rr.t.:.

 I5.D.       ,, H.l*m, z'            I    S.it,    S, Siddiqul F.         a.rot    .d        M. A,          H.t€||' ft+ ud
      FrBtn.pric              crpotg       ro   t{l{pl         trylDipdziE) toltosing .d.pr.id io                             ltB ii
      t   ts      Ptug.      N.wpr.tbptmdor. Brn. p'.ttdry. 26                                     (2002) 149_j6; Dor:
      10. r0      I   6/s0273-58!6(0t)00240-&

16.L. S. Pildsky, D,                 c. cod., p, r. EI, N               P.   vdo.n &              M,       Mmy.nd              R, w.
      r.di'l' D              do!.nirc rlc.'ror bindha in rh. h.$t luslir of ttiFy.rdic.fE
      shi&thdic Fri6c, Ar                              t23t-rBzM       sinst ph.io. Mi$ion olBraird
      @nogd4Jny              fird/' 8. J Pt chidrt,           t6a (t   94) t6-26i DOI:        I   o.   I   t92   jp,   164.   t.16,

U. Q, C, Mo& Y. F. Ch6 Dd S. Op| it, A jiDpk nErh.d fd                                       @'@[.rntr                 of   tioeojc
   hiB                ed ri.ir nc!b.ti&. tiw biotogiqt                  spl6      fo,   ut'!i! t,            HPLC-EC,            4r.
  sd        .ra (r     r89) t20?- t2l     li   Dor:    to.   t0r&n2G3205(89)9ot          t   6{,
    13.   N, S!trr4 F-        B@l {d             D.   J_   H.l-n, N.uEnmk l rd bdlNioEl                     .fra     of   B-

          OH-OPAT following cxDcs@                         b                iess in ds,     pra,@l i.p         5, (2007)
                                                               '!sid

 19. J.        d. Jong, U.    R.lad.n           E.   Vis!       md w. H. Mejjs, Dermin.rion of eEtonin ind

          lhydmryindole&etic acld                          in   urinc       b)   rcveBcd-phas ioFpair prnirion
          ohrc@8Fphy wim arcrin.dic d.rcrio\                                J   chnndozt.7 {193\a5-94.
 20. L.        Faiq A. L Nordtun!                 F. A,    Wiel,       S.   P.!li, C. tl:lldin ud G. Scdvrtt, Polirln

          .ni$iq @qtapnic                    .rElysis   oaqhl          Dr .rld D1     dopdi,. @pd           eops,         in

          p.ri..b brcd wnh crsior ndrclcpiiB                            znd ctoT:pinc.      Rci   ion ro cxrmpyhnid

          !jd. .lfec6, -,lah cd. Pt.hiet , ,t9                               (l9t)     5t3-544; DOt: lo.lot6/0024-

          320r(?3)90035-8.

?   I. T, J,     C6w, E. C. Johns@lc, A. J. Lonqn.i od F. Olen, DopmincBic mccheisms

          in   &hiaphmia: dE dripsFhotio .t$ct dd rlE dh@ pl@ss                                     ,/t,t   r: 23 (1978)

          563-5 67i     DOt      I   0.   l0l &0@41205(73)9003 t-3.

22. D.         Pick'.   T   P.       Sq D. R. W.inbs8d.           R. CoPpot ,        A K Mllhola     M. A.   kn;bb, K.
      S.       la,   J- Cor.y, ,- J.           B.lrlq A, BEi.r ed               J.   rkid, Indi   du.l vridion in     D
      dop€hiDc          reDtor @updcy in cloztqikt 4.n p^i.tu\,1^ J, Pt chiatry, t33

      0996) r5?l-r5?8.

23.H, Y.          M.lbr .nd M. u!dr, ,,                         y/rc   &tios of a$Ticll         mlipsychoiic   ds!    on

      srDrorcqic cnd dopa'rinceic syst nt, Prcs. Btuin                                R.!   171, (2008)   tn-191i DOt:

      t0. I 0    l6ls0079-6123(03)00909i.

21,X.          Xbc6,     J. L.        M.nim( L, M.ltl e Al:ti8q C, L61|. A. MdiaE dM.L.
      PrillaE-MdinoI. ErfisLia&l                        lrd sriel           D?   dop.ni.. Eepro. blo.k!d.          wirh

     hllop.ridol or              n*         mripsychotic druls          in patielll      s ,   etliz.Dheni.,    ,. I
     Pt ahiatr, 179 QDll ) 501-508: DOI: l0.ll92,6jp.l?9.6.501.
2t. S. Nyb.E L. Frd., L.   Elilsr!   C,   lhldtn ed   A,   &ik$r   5-rfa:   sd q dop.diF
   ,Er{q @uFlcy i!          Ihe   tiin8   hlM tir          A pEr nudy       *in ftFidd,.,
   Pt   tlspl@log,         lr0 (t993) 26j-2ni DOI: tO.lOOT/BRD25r2so_




                                                                                     t6
                                                                                                            257


Jqd 4fd d lbeliotrtb d        t1.No                                           r$e6rfi 4r.a              4BB

       Oraf Suppfementation ot Sea Bucllhorn (Hippophae
     nhamnold€E L. Spp. Tu*astanlca\ ftuit Extract Modltles
               Haloperldol Induced Behavloral Deficits and
                 Increases Braln Serolonln Metabolism
              F^rfi^T r^Tool'    .        HUss{rN sH^r|r. syED DtLN^w z
                                     ^s^D
                                      DARAXIISH^N JAAEEN IiALf, EM'           ^IlM[t     ^ND
                         |{.fub6d3fu6d!4d4rq6qlry
                          D@@ ot ot&rnq u4no4 eI xoa,
            et@t ol Lik si.rc br htuetuh aqbE !flvtr oJs'a FMt. stiptftr 3!t eaL. Lr
                       i krytun olPtd 3ai4d MtuItu et'an', tdd, atlcttutw.
                          urtt44 at1.d kM| e kddr tu


                                                ABSTRACT

                                        thl.,apqtu &@i^' L ,tu fvr{b".4)       {HRL) ecd! !d enr.r tr{
                                                                     iahEj9ifi6'jdPliqlqhukFF.
                                                                        jErtly&d&@L'ie^|dqi
   rbci'. ft { !*ff c !tr4be col@d       br   drqnndn &.fi<n (E6) tu l'ltld qlt     eE   Gtd      b   hd!
   !eft.trnBdff|a'd!ftdJeo.
   h,nulryF6m.: ,'HT) nd6i5 n a
   0'm.0'r0PMned304*gdy

   iie!drtq6rlE6ndbl40ndk[dyEishHRr                 F.ths&tr{sFrrhrHRL.ruphF!di'qdlFhj




                INTRODUCTION                                                             ri.'c M.try mrjd
                                                       h.rhh prcbrm (cafte4 diseeiv. rrcbrcni 6kin disF
                                                                                       .) r. gwiis npid-
lHippoph.e ,"oMoiae' L spp. ,,rt?s,o'ic4) IHRL) rE                                     opi4 coutrtri.! ind
w.r docuncircd in Aiii and Eump€o , Modcin hrd!
                                   s in undasEndinc                                      file. oYe*h?tning
rh. rol. ol didtry supplemenbriois
ofmeiulh.ilrh aid in rh. pEvenri
rncesins $i.nriric .vid.rce Bsvsil'btero $ppon 6c                                     in.luding trutu hrv.
hypd$si! rhd ocihin rods rDd ro
b€n.6ci,r phyriotosic.t rrd psycbol                    b.icha,",. InYeniFdols o! nod*n
!^dqld|orcsdh*
                                                                                         rrd   rhc biotoricrt.
 E4t tbrk!da!.*r Ebl6€ireqn
                                                                                 tu     or'   tsdd b4h4rt      .   rd   D.   h.,   1@


                                                                  b.iio 5-ttT dcr,bdir rhc mtrl6
                                                                  bur ion or icdrdnio dd ;b pftcudor
                                                                  djlmb rdi rh. rohsr or b'lop
                                      c5c   dn.rsi. Dilr.r



c,Dand K. dclr) Iis 3dN. ruredi.tu includ.crrceic,

                                      tros.ids. ic.,   irolrF
                                                                         ser buckrhon (t?pdrt,a
nirc. typbphan GRD and valiieL',. Lder ieeafth has                ru'tt6t,ht.l    IHRLI
shosn rhai over long perio& ol rine a nl h inlio eid,             (   Husrinab.d, S.kadu) of PakisEn uerc @uect?d in fie

                                                                                                              Lgp'idpkdrcDo6
                                      . i'npoirrir ro sood lrjllp.n.d                  lo Udiv.Aily olAer
                                      I s* buckrhon ii Azrd Kshmii                      The fresh fiuir *.
rherormoroik        d pulp   (roit enrd) 1i.1yrihbl..id
                                       oin.ric ind h.'lri
                                                                                                   bydhdineseds
                                                                  rbn          .r ser bucLrbdD. T
                                                                          50 b.iiies
rmm wbicb rb. juic. is   arnd.d.     R                            do& rne' w.thiis 100 b.tries and
                            5-hldrcxynyphminc (tlT:
smroi)       ir ieh?d from blrr lnd D'lp (fiui .n*D or            rir.d *.'d mrke a{e/. HRLjuic.
                                                                  nroni ofsc! bucknoE pura rh. o
                                                                              'o
                                                                  6y cd.id.d4 rh. *.r sld wisbr as &ll. Ir la;ni.
                                  , ir hr b&i rponqd              nit.d rh:r 50 b.ri.s or s.: butrbon muE ydd pulp
      diehry n.oirubrioDs or dru3 effeds oi rhc olc or
'h,                                                               ot puh did     m' indud. $.d3 EisbL         rb?   jui€ elurion

                                                                  r(  for   rs rdL   cdqriobrly ar r dc. or4.o ms/Ls
                                                                  body *rishr !r !r equivalc volune
                                                                  wcishr in elch smup of6t io a bilmdl dcsisd.




(DA)                                              pokdnl'     I
       Eepron wnh    rhen DA-D, mksonisri.
                                         s 10             rcro-                                               dilomAgb.Khm
                                                'noduhG           Uiiv*siry (AKU)         and srcup.houed Cwo       Et p* qa)
susgeded ro be impoftnr tor then effidcy lnd sidsct-                                               ft Gmb!.dr kfpr&
                                                                  rurc211r"C lnd rcl ive humidiry 55 + 5%) on r l::12
                         dopem'nergi. and $rcron.rgrc             I llghtdiikcyd. (lighs on.r r:00 A.M). A r-day edi
                                   d (cNs) rr,.h mrY
b€ ol rerevrn.e ro rhe   e(hpyEridil qmpron,              (EPS)   in .xpdim.nE.        At*      (hB period ind 2a i beroc rh.
in FrrLr).   sqdo*sic qn.n n r                                                                               ndiYiduirly housd

                                                                  .trr P.6pex cases (difedsids 26126126 cm.                  v:LiH).
                                                                  Food Grlndlr.l d di.t .nd re wdr

                                         ni!..vid.nc.lsn          lor rh.   tc.rtudr wm rll .xperitrtully miv..Dimrls.
                                                                                                             0.dmdp.rrdm.d
                                                                  ot Lrbonrory        Atrinrb (hnnd"     or   L,hnbry
                                                                                                                              ^nirir
                                                                  .il.   1996)   .id   rh.
                                         6rnd cluis.s iDdt
                                                                                                                                259


tuttu otfd          d D4)r4t'n,        td   D,   la   4rM


              (secnq nmuferurd unda tic.r*
       H.ror..idor
                                 en. P.riiin Lrd trt EtFb,@ td;vrt                              in @    oF" n.rd
l-.bdr6ict wa              jn 5.0 tru/hl rDpdhs
(id.$br. $lu'ioi)'vd!br. ro dcsiEd dos (r.0 fre7
                   dilur.d
rs h.dy wcights) in srrio. sruriod loe% NicD rnnc-
ro.! *.rc 3'(o rqie &iy b€tw.                                                                                   ividcd iDb 25   4ud
md 05:00.05:10 PM
6uG oa.ddiDi3tarion used v.s ininF rm4l inj.e                           ii (l'c c.trt. s!u3r. ot rh. op.h 6eld rrocy ro 1..v.
rions (i p.) conror rninars Eceived an .qrr rnou of                     rlr co.c aquac rdd dunb.^ of sluiEs cm*d vnh
vchiclc oo rhc $m! $redure. HRL
                                                                        s i.t'L !'. rhc rcrivny
                                                                                            of$hre inj
                                           dng dmininrdrioi             pc dol iry.d.d ,nd HRf,-FE adf
ro .x p.   r'n.dr!r   *h   D ! brran.ed d*'gn.



       Tvcnry-fou nimh wea rhdonly divid.d                       inro
rwo .qurl grcups nwdv. rdimrs in                      .eh 3roup) 0)
srin? inj?ded md (2) h8rop.ridor                      iijlded 3oups.
rh.s minrrs wm iqjed.d {ih h
013.0dg/ls body !.ishr (vo rinei
a.M. rDd 05 00 0sr0 P.MJ ftr 2 .drintq! *..k!.                            ! rh. dull fidn rb. fodr.l odd dnlly lnd m.dull'
codsr rinrrs *.r iqFd.d *irb srjn. ii hrufti or                         ohloi8.! oldllly is {ksrib.d by Btul rnd Hil.mrrr).
r.0 ml/ks b.dy r.igbr. on rb.6t &y or srud, tdc                         Th. ....b.llum *s oincbed aur by rm.Ds Th. biin
                                                                        dip!.d itr io.old slir wa pledl virh d(rl sid. uD
Kod.d          15   miDdB poninjerias of hrropsidor              .id    in tnc nold.d c.vity o, r bnin 3lier Olr&bry oucl.us

                                                                        '70.c'trdd.''d69ybiogoiioisbyHPLc-Ec.
vi&d      rNr.qnalsdr6 (six rdibrls iD 6.1' !buD):
        iDro                                                            Pl.etu xnpls w.r rle lord 3r J
(risrin.pruss'd(2) erim prus HRL FE (r) ilroF i.
dol plus    *rti      and (a) halopeddol p
r51!   .trd |rn dly or apqimenr              15   min eonibj.dim!       nlt HPLc.Ec DeErmtvlioB          oI   Pt6

                                                  diy of erperim.ir
by pmviditrg        nh *irh   a   r.isbdl        ,iont   of food wirh
                                                                        cf,tcd s d.*ribed by Hslerlrl BE; rRt 5.HT
                                                                        oid ns n.rlbol es *.ts deremio
iko noiirofd oi rh.6''            !d    15"d                            d*ciibcdby B.bdandcdrc'cu$l "r. A 5umshim-kck
                                                 nbs. ofiniriatb.dy     oDS ,.p.mrion .olmn or4 0 nb int h,l diaier.r aid
                                                 rpirrkd on rhe 15,i    150 nfr l.n3rh ws used. s.pamrid wrs ,chid.d by
                                                                        nobil. phs. .odhinids l1% berha&|, 00?lv! odyl
                                 r 70.c ror rh..(i_                     sodiun sulf.r md 0.001t% .rby1.o.dirmindetr ..
m.non or TRP. 5.HT .od      hydsxy,idoLrc.ri. icid
                                    5                                   c.ric r.id (EDTA) ii 0.r M phosph
(t-lllA^) by Hish P.lrdlrroe Liq                                                                                0psioDs|''m.dd
*irh Er.crnb.ni.'r D.rerid (HPrc.Ec)(ol                                 H   PLC pudp.            d.&dioD va
                                                                                        Elerdn dic'l                 oi
                                                                                                             'chnvld
                                                                        Sl'ihldzu L-ECD'6A ddErd !r ro orenrins lotciftl
                                                                        of 0.3 v {sbsy crbm .lEr'!d. vs d ac/ac,o Rr.r
                                                                        .ne .rdrdc). rRP wD &tmired
lt, LeMdr.lcnviD h LLN cas.



l26t26rl6 cn) {nh s.w dus cov.                                                rr rl'i! invsrig{id, $e   dd6         wre pc.n&d tr
                                                                                                                                    '
                                                                        rid op.i i.ld sde rslyzdl       by 2-way ANovA     (Epar.d
                                                                                    Mt    ol   tir a   h4 teb,t. 6t    D. no r.   tu
m.auF    design)     follor.d by      N.{ra
                                                 E oD rhc   qnricsir ol
bruii TRP ad 5       HT*eMi{ry-d                by   rM.viy   ANOVA.
                                                Netrfrn,K.ub       er.    or HRL-FE (1o% rr.patuoni 40 mgrkg body wcish')
                                                                          on prnna rRP, ba,n TRt 5 HT ao


                               Rf,SULTS
                                                                                    nfoodd!-                ItuE..H.ed
     Fi8r. I
           sbors rhc cffcds of oml supplen.nrlrion
orHRL'r[ (40t p4pai.rioni 40 mg/kgbody *eisho on
                                                                                I                              I
soerh 6t (% .h!ng. in body *.ish, sd dnul ve                              E
food ;hkd24l i {ri rro{.d wirh rcp€ded :dii.,nd
hdopdidol No ssnin.h( .ffd of
                                                                                                        I
{ 8rcv'h nr lr - 27: df = r.20: p{ot Howclcr.                             F-l
                                                                                                                     I
                                                                                ril
5i3Difraot rwq food    (r = 15.6j df= r.20: p<00r)                                                      a
qs   found              'turc
                  66 rdr.n *ri r.p€r
             'n                                                           E-l
whk sgndc.nr rn.mscr (p<00r) wrc obsrcd
group   ofnb      rred.d   v   h
                                   pbdu.sd stnificanr (p<0.0r)


                                   rpcabd hllopdriddl nlus
                                                                    ii
                                                                 {d.r
                                                                          :
                                                                                                                IT
                                                                                                               qt@atud
                                                                                                                           n
                                                                                                                          dtuMet

of BRL.FE (40% prcrldioii                 4.o   ns/ks hdy ycish0
                                 vircdnedr (i.                            d'trcls6byNG*nI.({Lk(.p<00
of bunb.s of                                   'cm'
             .re. .rcsiis' .kin6ia) aDd .iptonrory
rcrildy id no\d.trvibin. (in rsns ofnumb.r or
srturcs nos.d ii op.i ricld .rcm) in nr r.,r.d *irh
np.rkd sllift md h.lop.ridol
HRL rE (r = 2l.sidf . 1.20r o<00t) and hrtop€ridot(f
= r5.6idFr,20; P<0.0D *as observ                                                    !FN"d$'.               Itu!",-i.*,"
                                                                                                                   r..
                                                                                                                 .il
3is shor.d sisni6.sir d.c@es (p<00t) werc fond                      ii
con.ry, si$ifrqnr incrca*s (D<00t) q.r. obsc .d
                                                                                    -

          D"..-*-
             I                        g
                                          I      tu@k4-4
                                                                          3
                                                                                nil E.,
                                                                                                       3
                                                                                                                TIIT
                                                                                                                Lf         LT
                                      I                -
                                                                                                I
                                                                                ttJ
I
;{
                                     I
                                      5                                         ff                     I
                                                                                                                til
                                                                                                              @waPrehru\ 4

                                                                                                                G=   r:l s 3irkil
                                                                          ditr.delbyxlvfuq'xqLk:lp<0.0
                                                                                                                llsHi!.f.Iid'
                                                                                                                                  261


rd qlr-r.td e4          keb,h. vd 1,   tu..tu
fr.ftd    :rlin. lnd    halopdridol   iq                         indeNd 5-fiT syith*n id th.bEi
                                      ned of H RL,FE (F                                                        !'   ,   :} T|e ncchi,
= rTidr= r.20:p>0.05),insi$ificiDrdreroldrug(F=                  irm    by Ibicb   ,ri.r (or TRP) is rhousr,r ro         influ.d.. 5gT
1.6: dr= r,z0: p<0.05) .nir rc sisnif$dr i,r.rcrion G
= r r: df = t.20; p>! 05) bcrrcatr rh
Dtu on bnii TRp shs.d risf,ifica                                 n.d6r anido aci& (LNAA), *hich rffecr        rr of
(F = 24 sidf = 1,20; p<0.0D,sistri                               TRPftnspdi ii(orhe brlin, b{in TRP levels'hc hcn.e
                                                                                                           and
(F = 24ri,rf= r,20i P<ool) Ind s                                 rhc BG of 5HT !y h.*cr). r l* b..n susgAred rhsr.
(F " 16.5: df - r,20i p<00r) bdve                                by rhisnehidhi, di.raryiDtrylDrions mish i ucn..

rion ofHRL,Ft did dor,rr{ rh. pl.                                                                             'ionsrh*.dro3m
ligoifrcanr incEs* (p<0.01)wrc o&.ncd                ri.l.vels         x i. well .4rblisied rh'r iirop.iidor G doprmin.
                                                'n               D1   &..pror rnrlgonhl) prvei$ hypdsdivny induccd
     LrlE on 5,HT levds shded sipiricrnr .ffer of                by   rnDh.brid. dccEe, !p.i..n.
HRL FE   lF - 24.7; df = r,20i p<00r) .nd sigoif.rdr             dplohriod ,nd .licns r sbt ro@tr a €hl.pry1r !l
Gff.d ofdru! (f = t2.4;df= r.20:p<om),!dlisnificmr               fi. dormid. syd.n hdniomlly h
ioi.rcrion tF = 125: dr= r.20r p<0.01) ** oblered                                                      ny'"r. wrh rcsp$r
                                                                 ro rh..nrtomical siE otadion r vitr hi! d.y.ldpdd rid
rhd HRL.FE risufi crnrly incu*d (p<0 0D r-HT tevds               diarrniinyoh.d inrheonrDr of mororb.hvioi sri-
ib rp€dcd halop.ridor iljccrca fl6 w                             ,run, r ftsioi of b,!ii inYolved ii I
Epecd     di*   prB HRL,FE .dnrr
5 |IAA r.Ers !hN.d a s,eiii.rnr.fcd orHRL.FI               (f                                                  l'rYs b..n    shdn ro
           -
= 12 3; df 1,20r p<0 0r) aid ,isnifcmr .tr.cr or drus                                                    f rhr bnjndrJ. E&ry
                 -
(r = r7r; df r.20i p<0.0t) .nd                                   $udi$ hrve sho*n rhd        rhe   sdmirishiion ofh!top*i,
     (F = r0.rr df= r,20ip<00r) wa
'ion
HRL-FE lign,frcrDrry id.r.*d lp<o0r) 5 Hr l&15 in                in doprnine Dr     R.pbr     biodioS itr
r.Fded ll'lop.'i&r injed.d hb         {                          prclds.d neurol.oiic trcah.dd':'
rcpeded $rin. ptus fiRL.FE 3dninisr.cd dr The                    biidiis exFiodrB rG consisEnr trnh behividdt nud
in.rcr$ ii laliN ptu HRL.|_E,nd rp.lrdly r.ar.d                  ic, on experinenral snimals Tbr .hroni. halonsldol
n hp.ridol plur tlRL-FE wcrc .ompMbl.

                                                                 '.n4$Iedbymbrc.dby'.ndof rb. mdLoic''l
                                                                 b re.mo.ehjm rn. virhdnv.r
                       DISCUSSION

     To our   tndwl.dg!, pdlcnrill ml. of nedicifu t ptsnr       .xplohbryrdilni$     in gnps orru
s.. btckt\o6 <Hipoph4? ,hud|ori*r         ,, (HRL) .s .          ed *irh HRL,FE Co-adminBrlrior
di.bryodtrhlinlbemodu|rlioiof                                    ofa.o bs/ks b.dy w.ighr cdEprd.ly Fv.nrd rh. b.hrv-
b.r,,vionl d.6cn3 .Dd iDcc8.d bc                                 id in I rio. d.Fid"d tundn (ri3nE 2). ob4ed
byHRLnul*'nd$pp|.rudnio                                          efi.cB of cp.!r.d idfiotrdion ot baloperidol on
                                                                 b.hivioral defi.it 0rt cxpl,ii'b|d i
toDhu .od rcrcroiii  rf rh. 6io.dive idsrcdi.nrofrh.
itrs .djuncc in rhc dur.rid or rdripsrrboric rbapy .n rh.rfoE onsisrcm                     *irr   rb.   .di
roehi4brnic p!rj.d6rrlrrl Di.G                                                                                trnyordop.mii"r
5dye a , ,.ld rbd l.s iiv.!iv. meus rhri     ph.rmaco,           3r iorcns n jrvolv.d in        rhe   iidu.riotr orEPs        *iit.   a
rosic.h!1t.4c      (o pmvok. &roroftrsic rcspoisivenss
in sbibphsnir dudEs                    .ho riN, rb.r
                            srudies have                         nr   rcd wirh HRL-li E .outd   rcv's.    rh. behaviorul dc6cir,
                                   h;'ptrotrprti.lt
obsnrd fo.d in6r.        drrca.s (Figur D in d. pe
rri nudy vcrc.xplriubl. br $. frd lnd .rbohydnr                  ror.divnyburllso ii.ier*dh!!in TRPaddt-HT hvek
d.h dier cii infuen.e rh. rviitrbilry of nyprophsn ro            h de hlroD{'dor injed.d n6. rh. Levets or ti.c rRp
                                    r b'aii 5.Blrnl              inrr!s6, r,ve b..n ued.s an iid
mB d. s}lrhsisoa5.aT fouo*ibc r typrohrn lo'd                    nqorbnisTnPk!.kud-d,flerc
itue*r    in rh.     *bot. bnf4irnd
                                          M.ddi,rRt|dd
                                                                                        J@fu]!'|Fdrdfuc/N|l!'|do'Na1,@'

                                                                                                 Rf,Ff,Nf,NCES

                                                                        I    nnin.n.     (   M. B,krl. M A.3nd
                                               erproicd as HRL-FE            a!,li'y     .omponcnN or se, buckrhorD              atwolr!!
could h8vo a   lot     ial   b   innGoce braii    sroboin n.bb'              ,d',,!tet sieri*. J. Asi.             Food      cbeb  5l 1642-
ryDbpl'fhydnyliEblh.$b6                                                 2 Ba6idg.. r, Hris'. J L dd DmEr.J.2002 PE.
                                                                          ce$ii3 .rTeds on rhr .orp.sirion or sea buctrho.r
rid numbd or!trdi.s          hrve shown rh                                )!i.. trcn Hipparhde rhqni.ids L cv tftiaa
                                                                             sunftrlAgicFoodchms0]ll]-116
                                               hc syn.ps.rr6'. lr ir
dpddlhdon|adfrinktrdionofT                                                   tHrypophe tha6bte'): r                               pt2nt. Ho.-
                                                                                                               'Inin4e
lryds 100 nin sncr inscdiotr (6s an                                     4 zeb,     ,\   2001. chemi$r       .'d nuriri
rcDecriv.ly) and rnrincd.r rhB I                                          S.r buckrhoo ruicc. PrLisbn J Nuri 3, 99106.
                                                                        5 sh,i, A. H.. Andrd. s. D. s'bii M.. adl S, lO iq.
d'Krly virh rle rYiilrbihy 0r c                                              r   ind B'rol.     F. 2007.    Bicb.ni..l             odririoi.l
rRt $. sun           orwhich is didaiy'lxi Firdinss ofrhc                                                         '.d
                                                                             cvrlulriotrs ot s.a Suckttq! /tippo?ta? .,o,ro!
                                                                             Lr a. vz &d.n zn4 rsn diffcrent loQriotu dr
                                                                             P.[i!r!n Pakisbn J. Bor. ]9: ?059t065
                                               .n.d   rhe uprrkc   of                                               Usitrs sca      b!.krim
TRP rh. bdid rnd.dcqEody                   i                                 oil in rEriDs     bon'  rl, n7-l$,
                                                                                                      Sov
                                                                        ? srbn s. M- Masood. l{., Hayd.l.. Kh{, M a rd
                                                                                               ^rdt
.d     sppr.neded uirh HRL.FE (Figua l). ov$il
     i,$                                                                  Khaliq, A 2005 ElcmeMland nudiord analtti! or
                                 ryadiviryandbdin                         s.2 b!.l1ian l4i ,aphE rhannoi.t4 L spp turN*-
sroronid m.rdolk6 sosg*t the posiblc .ol. of nedi.i                       ,,,n?r hdria ofPrkk[Di orisii J. M.d Food r 5l3'
Dr Fllnr S.r bnckdDh md i's frui
                                                                             chend.rnalioi ot losl senotyp.t o.                    ttPorr,.
                       CONCI,USIONS                                          rrom Nonh*n        aer    ot   hrisbn.      I   3'ol. sci.   2 r5r.

                                                                             ttzrdla. rr,,ro,/d' r.            .hffisrosnDhic mdhods
b.hrvidnl dericrs. ln dddlrioi, HRL.FF rev*$d                  b ii
                                                                             m.diciie rnd ph,'neolosel efikts. J. chnn{og.

$r lwil'biliry   du. ro
le'd to rhc incrcased 'li.r,rytHT syirh*r. Decr$.d
                      bdii 'ourc                                             olosi*r cr.ds or Sd buckthm (d,PPoPro.) lipids
toodinbkslnd hcned bmi"TRPcrhibib an idp.r'                                  Trcid,lood s.i Tcohnol.lr 160-16?
rive 6le ofrftitionrl $rces or s.                                       ll   Bnool r ,nd H,l*m, o r 2003 s
                                                                             ag.nnfr in ll. .:pEsim of b€l''id,l dopmikrsic
                                                                             $p.GNirivig in sub.hMi tJot ridol rd.d d$
emph.stins rdl. of rcruronr

                                               .d ir furucnddicr

                                                                             Iftlnlipqthd'c'luli.eD:mbgqis''d5.fiT'^
                ACXNOWLEDGEMENTS

                                                                        13   Ichikua         r lid   Mcxzer,   s
&rion (PsD              univcBiry or Ka                                      *o'din  (lA) Ec.p'or .sodim o. ti.psy.b'rc dNs'
                 'ql                                                       indu..d dop'ni* d.e in d {nnum d rurds
rhc   c@nflrion of M. chulrm Nrbi                                          a(unb.N. Bnin Re. 353: 252'263
                               I hh h.lP iD                  indc       11 Ko'dl. L, s'ndyt, R., vscner
colledioN sudeys rnd in rhe coordindion orvisi6                            fi. 198r. rhr dleds or lrrypiophrtr oi hrlop{'dol
                                                                'i         rndu..d m0vmenr d'srd* in rh. nr. Lire s.' 4r:
                                                                                                                         261


rwt      oJtd       od   hea&ts\ ld     t7. No   4   ,M

                                                                       :2 Hrhcm, D. J, t990 rtrj.crcd ryprophan iicfa*5
15.   AoAc. 1995 otucial hdnods ofamlyi! of rh. A$e                       bdin bur mr pbrm. rryprophT teh htre in dhsol
      ciartm or Oficial Analyrjcal ch€nisr. rj,i .d. A$c                   rcd.d ruh LiL s.i.47r 97t-979
      cnriotr   ofora.ial Anatyri.al chcmis6, arlingb v                23 Bdool,    F., Ahh.d, S. and H.ten, D. J.2009 Didary
                                                                           ruppr.n.nhrions ot mino .cids Evid.n.e for
                                      n. D J 200t N.u.                     .trhii..d &dondsic tundio$ follNinc haloperidol
      Io.hmnal                   pmrits or l-o.NlphrhyD
                        and behaviodt                                      *irhdhwatin mr h.d6t pr.fMd .onex. l. co[. pby_
      pipddine itr n6. J. co[. physicim. sulg prk.lt 50-                   shi6 Surg. P.k It lr9l4s.
                                                                       24 Krpur, S. rnd Rimitr3ron, c
                                      . N. H., X.nil, N,                   doprmiic jitdim md i6 rlewe ro ehizophrc-
      Ari, o., saify, z. s. and Hrlcd, M a. 2002.. Dif_                    nh an. J. Prychidry r5l: 466-476.
      Aanes in $. .tTd orhrto!.'iddt snd oloapiic o                    25. Pqc.ddu, M. 1.. Orisini, t., Mdc S. and Bissio c.
          $ddh dd dolmii. mdrbotism dd d cn,
      brain                                                                 1935. ]H-SCH,23390 bindi4 sir6 in rh. d subsrm-
      FbEd ro.xrnpytuidal rmclids h rus, M.d. s.i,                         rir nigfr.vid.ic. for. pEsyDrpft lealidim sd
13.   lraleb, D. I, saiq, z s., siddiqui. s., B.br, F. td              26.   'nn.djonbydopDin.Lif.sci']9]2L]21
                                                                             Utuovq N. A., Odsby4 D D- Ap.l, K , xtineq
      naleb, M . 2co2b. Pt rnd p.6ryi'!ric cpons                             A. J., H&riEi, n.,nd s.h4k, H. re9t. Msptmd,
      b I 0 Mphrhylpip.rzi..) folt*jry !d.p6.ion ro                          ric $udy of synlpric t tr m iD rh. 6r qudaE md
      fts       D   d    Prog.   NmFy.hopl@.ot            Biot. p.y-         hipr€$pl! !n&r hiloFridol rF@nr. syMpc 7
19    Hiren, D r.     Kb.., N. H 2003. Etrbr@d d                       ?7,   H.lp.rii,   R.,   ctr'in, ,
                  'nd
      *don'o,^ rE.Drdr d.p..&Dt rc.po$3 fol*in!                              i.do.l difi.Enes in ri. itrdwrior or b.hrjort
                               tu p,r€. N.uDFrrlF
      vidlddvd orb,]{'pc'idot in                                             oed*sini, by eord's.d tud *irr ! 9pi.:j
      ph,mel  Biol. rsrbi!ry ,: 64s,61.                                    Ermkpri.. P.'rlsDlmelocy 93: 136]9l.
20. subd*4 v- HoE \ r- (cny, J , plditM. v-                            ,3. flddr, F. ,00o. ltyto9hd-fiE dib: pfirioJosiot
    z.Gidq L_ F.l.Djc.li r !d Hcn| c. 2004. rr.                            bor ro rudy bnjn *Frorin tuF im Nds r,t46iot.
    .fftd otryFoDtd d.ltdim d rhr.dioi ofilbdi,
    &r in Mx,8or-rand tu Eur l. phmel 502: to9-

21. FetM, D J. t9$. Rdt of pcue,.itrbiliry i!
    mr of rd6[iF bi6ydh6& in bnai. pn jiot.
                                                         ,_L
 ORIGIMI      ARTICLE


         Dielory Supplemenloflons ot Amino Acids: Evidence for
         Enhonced Serolronergic Funclions Following Holoperidol
                Wifhdrqwoi in Rot Medlol prefronlol Corlex
                          fad,   Bar@tr, sho,ibAhired:        ind Dxlkh3hin hb€en tu          4nl

   @l.c0Gr iMlgab h .ds6 d o6ny t@r.tutu mh di L-rryrorrb (ro) and L-vrrio (var) i. 6
   reF6ynrtudb&p.ndrtu                                     k6brebd;e;ond
   r@n3 rEps).d xdbn ('rr.@o:         rHD ruubo. nr@tddd os h;;cj. -,_--
   P'erddnuddsrudy Dqxtud
                            m      b ei b6 ri &D *s
                           s'., o, r! oi rntur oF d skpe @ dods; jo-!,od;,;
                              'id,

                                        ,   bc r b,   TJrli       e, dd4 !   or hs



   ra d$ 6!ffi. :oni@. rp{.o                                                  ,{c              *dd*         ; t i ;;'t;
                                                                                       "n


                                            4!4a39__99!31i!q44                  4lltu                 sd.cn-
                   INTRODUCl'ION
                                                               Trp in !\€ cNs.rl       ln.    adminBtra
                                                               omumplidolg|yxmic'ichd|.'m*|o|ovabbEinTo
bimh€mdry, 0l6tary ompon.ds tike stlohtc a                                                      roil. and ib haior
prcbomic conb^b .n6.1^9 i\e perrpheEr antro etd                mtaboio s-rrydroxyndoraa@uc aotd (s.HrAA), r@
bdan6 inrru.m€ rh6 avqiralirit or the mlm eid                  0@!6 in a row omFnlraton (<1%) In n€i di€b4
L.rryprotiian (L.Trp) ror tto cgnirar N.Mus syshfr             prckohic $u@s, rn od6r to !.r E@s3 io lh6 bhln, ii
(CNS).': Th. synh$b ol 5-hydrcxyt'9rafrine (5.H1               fruBI smp€r€ wi|lh o{1.r LNAA vb
sbbinP d!6         i@m   ib   p@Br   L T@ in    hd@.          upiiko m.dshn. Low pforeoma di.ls swav tE Erio
rhe BIe at *n!l.   seloe4ic rere syn0'*i2. t'oir              ol Tlp b LNM in tasr ot T'p, s
s.nr oepets   upon   fr aEl.urr, a ns pe'@ T'p.               lepded ido rlE bftih. oola'y supd6midid ot
                                                              T'p en rike'i* i'@  rh6 E io or To lo ornd LNAA
a.1ireupla|@dd.tonismsp€.i|iclolTrpanddl*l                    dd dtdd r'p M ad@6s6 *n6o vying id €nry itu
L,€e Neutar An'm acids (LNM) rike varire {vaD.,
con*queirly, tho €rio ol T'p ro rhe sun ol LNAA               A   Bdn.h€echain Anrc ,aid (BcM), L.vor mmFr€
{€[n. r.ucrn6, i3o.!cln€ tGine dd ph€nyr.rMin6)
                                                              ProvlouslY   b.en shoM
 t tupn!,t tl Dhd(fitl uti\sr' ol Kqurt xtNri                 3t?dn6sls5   convecen ii i3 ,opodod ihar Tlp                r@d
 : bplnat !,t Ftv^htry c@htd LhhlIr B6pkr, Mdr

                                                                                                           0la6matpTLNM
                                                              6!0. ih6 nsestion      or val   ca6*   apr
  bNfuld@l&|&L'|.                                             p|asmadfuenHhns,incEa*s$
                                                              b.ain.add€c€asg|hebEinU9rak.and|ftl!oIhe
                                                         __-L

 amno acid Trp. orat BCAA vat hav€ atso b.6n               uirwclt (AKu), wef ercuPhousd (tuo Eb lor
 adminiieEd b &hlzopnGnb                                   c!96) in .n r'jrElt@phg ..rrcnmenbly ftI€d
 dt'!'dsd@nuE$D€bnbfurue'l'g/dl@                           .mfr (mbi.d rmpeatuE 21+1!c aid €tdiv6
                                                           nlndiry s+5%)       d.     12i2.h rqhr/dad( cacb. A s€v
 Ihe abitiry or ai0prydholjc
                                                           ac.riafarim leriod        G   arbmd b6roB dimaE re;
 *mne€a * $dr dr dorqmine€i                                                          Albhilp.'iod'a.d24houG
 suggBelobeimp6fui'1o.fi€n
                                                           oom      i   tanspamr Po€ps^     q9*     (d


 such6 haopeddo
 doFmine (oA) rccaprors wtlh hen oa.o, Mbsonreric                       oxpdiho.hr prcr@k
                                                           app@dbyMdpenom6d.l'icllyl
                                                                                                                      $r;
 @panredc    rd solondgtc reuMs in lh. $Js,                rh. inronanhar (us Nariod n srh cou@il, 1se6t
 whdroybeo'€|e6n@loth€adeps/syndrcn.'                      .nd hd @ €inid @mmiros qd
 rn6€ ii arso.ulq€ni€ .!id@ tor irlpoiad o,r!,5.
                              pS .ynploms, ,s
 digph}€dind€eb|6P3ynod€|]nEb,r'|tha'b..n
                                                           otu$ and Injdos
                                                           usal. pmdEFd 4 nr€tub. .6p.ds or 5 mshr.
 6hM hd dnurarbn or pF,synap                               @
                                                              'nldd 6b 'dEp.rironaEl, (r.p.) ar a d6o or 5
                                                                    m
                                                           ne4gbodv@iohiiw@furvb€lw*nom.1o:o0e6
aiboonEm dr .ataroFy thdu@d by dopahine Eepror                            houE ror coilt.uousty 2 w..ks
brockhq agenrs kB hatop.ridot,,, esoesij4 a n@d                                                         parcd    bD war.r
flrncrpre lq aratnlng cliitoatv .nodjre andpsydolc            mrm.eEd @tuno) add.d n dinrhE kaE ar a
                                                           (200                                 'n
asenie wi'l re*er or no EPs.                               do* or 2 hq/d (w/v) weE adnini!;tored MIy tor 3
rheEbp, ro hv63ri0€re 6.rar $Hr me.rEnim in                                                  in.rs werc inid
an'mars r@ivinq chrcnic n6ubt6pric rh€€py in                      srine,n vorws or r m|/rg b.dy we4h ffi 06r
                                                           'irh
                                      pFC
                                  re o€niriw,              Exr.n@ibr Pordor Anim& ot 6hr (os* NaCn
ne96rvs or pGitirc sympron! or scnizophreni. tr            aid hrbp€ddd (5 mgaq) roaGd gDup6 @G equaly
c.nve6et, $6c hs so dariye                                 suppr€msbd wirh vat tud TD        In   rha
effdls ol aniipsrrholi6 wilh oElry 3upplemeiiod an no                                                   l2mgjml6s|rly
adrd .qenrs s rho rel.as ot s66ronin in rh6 hpFc          pr.pard h bp walsi wdshour pa/d                o, ihe dtus in   fte
bnn reqion. rh. nPFc h r6p.ded haE sEniriont
                                     .Hr}. 5.NT3 and
                                     'o                   symprn' a.liviri*
5.HT7   G€pro6.D.r   n.doE,   lh€ o                       hh            (home €oel
h €n€€[ur.] s.HT r.wrt    in lh6 npFc region    6   b€           J0 n{n@.t {d nNl {
                                                          .6!5h95/
.rp€cd    ro haw signiri@nt 6ndt5.n    rusldnd t                 r! @€ In s€c/ 5 hin0t
                                                          or rar.&1,
                                                          6qua6 cGed/ s ninet .ruiMnFa. cabtem,
nE pcenr dudy wa3 d€sgred Io td dE effeb ol               dolii6daslrEa@pbrod6i
o€r sdppreftnbrim or nino &j& 0/araid r'p) tr
boh.vjtuEr €spNr prMa aid b€in mPFc rD                    d.romhatMs         G€ Mid        od by srnlt rehovins       Eb
                                                          (n=12) r6m rhet



TD as adluncls ror rhe rcatnonror EPs symproms or
lhe .euoLeplic ase.r h.lop6rLdor.                         po      ion was   reoded   by   mo$uin!       rho rime liom rh€

                  MtrTIIODOLOCY                                                                     3 Felhi4bi or
                                   I*Ege{'9h'             hd|.E'ib|allel2{Eksoll@h
or   r30@ s   d   aind, puEnsod lrcn    The   &a r$an                           ro   moniror      6.kly ch..€6s 6
                                                                  __L

 €rarepsy and lM lihB ro     w   thd.6war or tess by tho        nis                                  RESU!'l.S
 was m.atued A oul.on riho or 1S0 e6nd6 w€s
                                                                       Fiour. r sho$ rho ertdrr             6r orcly Eupdemeilsd    amim
 enpoyed i0 4ch rat in t[o tGairnein, RllE q6€
                                                                       dcids (var and TD)
 €Eeeded by 13o .@nd3. sr&re on
                                                                       admriisdid (ior 3 re*r) or h.too
                                             pbeE a.d r.ln             s nEx{q aid 2 @Is hsropa'tdor ot6
 mPFC Trp, hPFC       rfiT aid     it6   m.iabottd t@.t$
                                                                                                                              one   wk    ot
                                                                                                               dciiv|tyina,ani|ial
                                                                      .tuiMnd {dniy box                       atu (ar.r.@ B).
cmh'nd suppremdario              ot v6tand       To   ror 3 we.rg.                        ^)
                                                                      lhoe w6 non-signiti*nr V+T €jt6.rs                       (F-1.4453i
                                               *k    ot witMn*at,     d'=,'30:      p>0'01)
                                                                      lF=24r !1,dr=r ro, p<0 01)              ho,Gq
hmod abry dd€d ar -7oqc ror lhe d€bminard or Tlp                      (F=2    xerdr=r 30; p0.0r               ) bd@n v+r ad dM
and 5.HT merabollsm by hioh p€dorhanco riquid                         .lt€.i6 D5b obbrndd on rocomror actvry b on;
chmmarosEpby wi!\ 6 €.1roohm car derection (HFLo.                                      sho4od ds^'ricanr v+r sfiocr
Fc). P asma sampres                                                   {F-2s on drr30,p<o.01). nM{ s
                                                                      etied lF=2.9976, dr-r,30. p>00r) ad s'onrf4nr
NtuEnediar tuatEje Di!@iq                                 pcttrrar    dbndon beksn v+T .fld dtuq oid (F=r27.75:
                                              or M.diat
cdelen'Elsw€cde.pibtda
                                                                      &rro. @rr.i3             tud     d'at   €paiod     *nini!tu        or
d€sdb€dbyBah.|andHaj€6n'lThoecb€||Umwd.                               haiop€dd.r      d    a   d6e   or 5   ms^o donmmdy (p<oot)

.avit   or   a bErn 31.6r a      fin.     shino      tii€ wrrc wa!     .Jscrd drs. h conrd.r,          ro   |owri! on€   ie*    wrlvawd
                                                                                                 slsnlrrdnr tp<o ot      )   hcr686 @ro
s cos or bGrn. Dgsicd bdrn Eglons             &re    idendlod   wih   obFrued in both erin. inlod€d and halopeddd injecr€d

                                                                      6rped've wals rear€d
disered dr wi|n $€ h€rp 6i lhaD serp€r hitaro6rt                      {p<ool) de€.s..
ed do'€d ar 7o'c in od€r b *sy li4enic sir16                          i^ided haropqidor EE @ny                 ldd
                                                                      .ndlEl'Mgitrlladyl@l€d3!li*iq.dedds
HPLC EC dereminariN o' or.gna TD. ban mpFc
Ttp aid 5-NT n€taboriLs A6in sanotes *€r.                             (or 3   eekr)   or   h.rope/dor .r . dce       or 5    mq^s sh@sd
homq€nized 6 d@ b.d by Har€m.3 mPFc 5.f17                             tui*isnfsr vtr 6tr66 (F=2 e2 dr=2,3oi p>!.ol),
                                              d bv HPLC.EC as         srqnli€nr 3in0r6 drug 6tr6d (Fr7120.i: di=r30:
                                                                      p <0.01) .nd indsnrrkanl inrdGcron (F=14.103;
ODS sopanlionolumn 014,0 mm inrdmal diah€rs and                       di=1.30 paor) b.rws.n v{T qnd druq onecE oaia
                               n w.s achdsd by
mou|e pn6e cdraining h€rhftr (r4t6), dryl ediun                       v+r ener (F-5537s: dr.2,3oi p<001), siq.irh,^r
sular€ {0.023%) and EoTA (0.0o3s%) in 0.r M                           3h9r. drus €rd {F":47.4i dr=1.3.r pd.or)
Arosphabbln€ro'!F|2'9dtano!.Elil€p@u6                                 Jqnifor'r iiEEcijo bdren v+T 3rd dtug €nd 'nd
m0o-300o psr o ShiDdu HPLC pu.!. Eldc
6neni€rdd*1im ws a.ni.!€d                on   snrodzu L.ECD-          ttopdbd ad.hisr.to. or har.r€
6A dereob.    d   an op6Ering pobntrr or 0.3              v (qret     5 mq,ro              (p<o.01) pbdu@d 100% €blepsy
                       an ,q/agc r€rr€nco srdrod.).                           'roniflenlly
                                                                      Ln 6b ohrry supprerenlgd {rrh ,.14 var 5nd Tlp wh€n
llp   was d€lom nsd   ii a sepaoie run d M opd6tlnq                   comp.€d *$ simila.y lrcat€d salina Inj.d€n €ls. In

srairsiicar anaLysig: D.h on harope.idorinduc€d                       haropeidor no 100%
catalepsv  detcc ol moio. elvit in   and lamiLiar                     haropeidor inj4ied ars oElly adhi
                            'l@l
€nviMmia re€ slotstc'|ly salF€d b, ttway
ANov GeFared moatuF d*isn) lolosd by

*rii. d @.r.d               in.
                      halolo'idol                                     {ithdrawa|olh:Jo9€ncc
.naryzed    by sway z,3-ANOVA. tu               16   Mpaisns          dMlt 0n iems or rabncj                  b n@       ond   nuer      or
                                              ldip<0'05w..6           squ.Es crc$ed) in 6rs oralry suppl€
                                                                      var and Trp. TheG sas insionirieit v+T efier
__L

  (Fr1.174.drr,30; D0.0r,, neronircMr st.qro druo
  .lJocr (F=02637: dr-r3. p>00r) md.rqdri€ni
                     v+T d du .nd {F=765s:
  drr,3o, p<oot, .n0 iEgnn6d v+r .[.cr tF{.743:
 dE2,3O, po.or), rrgnifii*r eneb d@ 6fid
 (F-6s.r0€! dr=r,30, pdol)dd rs
                     drus 6n6ct (F:37..3r dr=1,30:
 p<o.01) m di day

 Op6n r6rd erpror.bry acrvrry showod r€n,flcanr
 (p<oor) rmca$3 ri oxp'onbry dFiy bn@hs 5.
 d.yo|sd6wa|IMh.|@ido
 o6rt ued€n.d.d ,i[l mE4 wr d                r'p   ror 3   E€b
 Flourc 3   sh.€   rhg ofi@E or o6ly $
 acrds 0/ar and    rtp) totbwino on. reek ot hdrop.ddol
                             rro, mPFC trD and s-HT
 Th.B w.s si!niri.!.r V+r €fiets {F=1s.707i dt=2,3o;
 p<o.or), 3i!dT6d i.!t6 dn4 etrect (F=13.0,ai dE13q
 0<0.0t arld doiiacld nbEdio. (F-?.6€: d=t3q
 pd.orl bdwd v+T .nd ddg €thcb d Oldm TI!.
 s|gnmd v+T .n* (F=14,651i dr430i o<o.ol),
 ionsonin€d sinsr. druo onsd (
 p>0,01) and.iqn c.nr riloEoilm (F=25.162i dr=l,soi
 p<0.01) were shown     b.tw*n    v+T   dd   drug 6tr.cr6 on
 hPFC T'p. rr,r.l4 anarFis m data ot pblm T'p
 sho*rd diqnin@nr (, <0.01)       i@3
                                   in Ee€r.dt
 $lm i4ed alr ddry rurddEd€d rff' .,'d r,p
 ,@ r6p€tu wd& r!!Gd @ HM. '/€l       ddid
 1p<0.01) ieas    w.B aL,o ohG€dsd ii EpeEdry
                  9dp or E6 o€ly 3upgtohenled
 h.bp.rrdoJ inieored
 withv6|andTr0*ll.nomoaredw
 rcared Eb. mPFc rrp $eed insisntl€nt (p>0.01)
                      srine ht€cr.d f.l3 o'.[y
 ldrod Ets.  Hffil d€hird 0)<o.0r) trls ot
 nPF€ TIp   re oo!€r.d i. €p4bdy h€rooe'idd
 lij&bd srcup ol Et! @rly duppr.ftnbd rfih \ i rd
 Io lhon @oparcd s{h E pdi€
 Th... Y€E               v+T.fiei. (
              'ionirdsr
 p<0,0r ), slqniraani dnol. drus €fiad (Fr31.04i
                                            d.1,3oj
 p<0.01) and sionirh!^r  hbGdion (F:r26,13i dl-1,30:
 r<0,01)   bekd     v+T sd d.aq en€cts d hPFc s,HT.
 tub evz.d id     mPFc s.HA ds4d .h'ffenr
 v.r .n4     (F=r3s.6q dE2,si p<o.01), s'!df.!d
 .incr. dtoq sffd (F=23.2s: dt-1.ei p<o.01, d
 .lCnirrcMt id.acrio^ (F-203r: dr=r.30: p<0.0,
                        ghowed$gnmoanlv+Toff{t3
 (Fr26.e1 dE2,30i p<0.01). sisnm€
 (F.23.37r d:1,30i p<0.01).nd sig
 (F=25.?3: dl=1,30: p<0.01) helven           v+T    .id    dos

 h.!|c.Eyr. d          dalloa brdo PFc s-Hr.'! ib
 mrab.ib      shorGd    3rs'fEd {p--o.01) hcc€B h
                                                                    _L
                            nrr.@d Grs    o6rt     suDdemonrsd        The rcsurb frcfr lhe sacond pan or       fle nudy sh@od
 r6ar0d h16        sEni,i6r(p<001)    inc                             rnbdin mPFo Trp con6ntaron Md consqu€nlty bv
 H AA    *ere obseNed tf, repdEbdty hatopeidot iniecrod               an erovarim n b6in hpFc tevels ot s.HL 1tio6;
 Eoup 0r   €b o€ y suppraooirgd        with vat md TD         *t€i
                                                  tu                                                           obupso'a.iru|s
                                            r.d          NoN6L
                                                      eDoss ro drus sm&dwar €pisd€s ii be studr
 6,eiiienr (p<0or)                                    Ih€* rindn$ c*u Ero dhEr rcpo.6 a6, dindl
 rcp€rcdry harrp€idot        hj6r€d !q]' or nrs d.[y nolwmedo|drcnt*hie'h6etstmts'in*ibm
 eupdemn@d wirh var          and r.p ,nm dIloa,d *rtj h}'€lldjMingol6d@|dop€n


                         DISCUSSTON
 Tho tp car efied oJ adhhbr.dnq a dopamiio r66pror                   dordrhrnalion or ban Tlp ravots an
 anragonrsr . a suPpr€sio. oi ep.nll                                 rarioE of mno &idE, Prma rr inc
 ro@moror behavour d^d .tioLta on d


 pc6ynapic dog.mino o^.D.                               .nbqon,gr
 hdbp.@dJcoolsfrg^oljor    'ecepbr
 cinrr (r@) d.r€pros.ntc .it* in EB 3d                               .dh|h9@rcE4.yem.
btuviour sup9c*rrE €n6cE or hajoperidot did                    'l.
                                                               nor
rhow brel@ virh 6p.ar.d dG
                                                                     lnvollemenl h n.udroDnc           shon.bm Epstd
                                            d   adm'n6rnrM      .i                            'nduced
                                                                     rai. spp€ains rsdlv€ dysktnoelE and in metoE @ ol
ha|oDgddoloxhbibd3lgnlli6nll@
and dpbBroy acrM{os and dtd nd induG carato*v                        lrudbs hav€             o. cs   d   o h gh   dc6 p5 ms^ot)
Thg 6|lecl o' g€dua| dal|y wjlhd€,.j lrm |onors;                                   'spodad


lionind fi.qeisiv. iF€se h                                           ,     Ims Lsrho irc'€dso
acriviry 0ar6cy ro frd. r.d .xpro'arory          adivily' h r.r3.
                                                                     @mn6. rk€ ob*rydMs                   aE   rrtMd      n $a

suporconriMt or c.nrar doramin
                                                                                                            ninedhv;
Th. .ttods o, rep€€led admrhisrarion ot harop€ddot aG                liroig€r 6r.d up.n rho corlc.
6rpla isble in iem3 ol 6iihor an inc€s. ii rho                       and ihar ihis erer h n.di'r6d via 5.Hr2 lD6s,brv s.
raspdsiveness or pdsbynapric 5-                                      HT ) €eproG.fBa n $b g[dv, soe.iar alronlioi
do9am E D @6pro6 or bo$ r'.€
augmenH moror behavlouB r€,rd
.neriyMes or smbd€nddrlc a3 w€[ 4 p.sworrc
s.HLr Edprod iaib*int                                                96iw0syfrplfGo|sciieFhlsiil.
Mho acids {ih druq !$nEwd             .ffd                           m. indudiM or EPs tn. Dl*nt studv $FE time
                                                  Ofer auth*         r,€p.n&d ilmes in s.HT 3yntleb totei.o th6
hs   cp.dsd tEt fE a.lcaEr€pbs.nic            atoefrecr was
p'odEadbylh6|q|dpplicalldol5.|{Tidol}EEoh€                           .fiocr. in nPFc bEin reobi.Ih€ in
r.gion sugo4nng $ai rh€ .fi..rs i:r prcdu€d by th€                   m'k6d in Eb €Far.dry intocr.d wr
.lLmularion   ol     sdmarodondrrlc
r66uris show rha! 061 3lpp|3madar ons or           ff    no aclds    6nsnlarion or    s+ydrcxyindoLoa@rio add (s.HrAA),
                                                                     l\€o'inadm6hbo16ols.HTwsga
                                                                     nPFC or €lE niecr€d *rrh haroos
or EPS   iMu€d      bv haiooondo . ( is wen     kwn tEr EPs          5 hgn<s in rhs prcsnr.tudy
                                                                     Thi! id.D€brim s b. rurtrEr ffriqhhd as Ta
                               Funhom@'€lalepGyo'                    adninishrid i.rru.rcs b6in tuditu rhoohr !o b.
8up96ion      in   r'ffobr *rivit en b. anbqeizd by                  al|€asl'Jtytrlol|.dby5-mR'I^'sudeth.6
                                                                     €nb€b|@*edbyd.adnintiEionol5+lTdb9s6t!
                                                                     and enhaned by e'i.j.crion or s.frT Euprdk3
                                          ondrlic aFIan        i.                                nss, ihc drc^et
lho rcl b€ln by m€ans ol va aid      np   suppremenrarions.
                                                                __L

3ynm4i.odMebsmind6b-oadinhEctoi
yrh por.ynapdc Geptors. .rh. elr4b ot did.                             lyn   du m m       ,d hd d.   l&q
                                                                                      h                    rleq   .ri
 bBin tundro 6 aG        inbdi^o       ro   .t@i
           d{@s.d b6at s,HT and $H|AA tovats
sig.rflcanlly
roodri, ar10. i^g3sr's t6s and at
€lpoor€ry) and €nained ar rhts r6ver tor aiolh6r
140 hLut€s.e nae csutb *ru. 51w rEt rendi or     5 {o u. sd r, (bi u. Kd N, ai o, $ta.
TrP r@ s. bda'd dtF.ctd dnnu6 &@r.d
dc. or tHT in rE d bEh. orF. O@p or .urD6
E3 Eptu h .dnidturbn ot r@tre mrtuE .l .'|bN'$y6's.dql{l&riJ*Mb
                     $rcbii d.ddjd in 6o 6r                             r1r{$rDnrrcn nEl
                                t3chizopn€niarko                     'o
bhaviour ws ebca'baled by {l. rlpjree mixtud
dld?lno hosl ini€dhs I&u[ ol r sdudymrhat
addron ol TD as B suppt6h€.r rd rhe chbirc
halor.'idol r€aimnr adenu€r63 th€ cd2leosv ln 6b
wirl rh.   ftonii.d            in   bEi. mPFc 5.HT synrh*is.
               '!4
nF tnpon fndttgi or he               srudy suppd ,re i.,€a l,Er        .cdffiret@b@!!ti
@r .dminishlrm ot annro a.i<,s i
habp'idor wibd,aw.r r'!m |dor.6 dminituarjo^

                                              rr5 in nPFc, *nich      hhm*he.p,m rd Mqtsd6 shi Fnu)
@nvincingry suogesied $ar rha         dl. or s.HT fomatoi             d d@!nh. (q) re..rbn ri h d rdi tu &, je
                              rh6 .v.l.b tiiy ol circ,rahs
oEuer       TE   i4ers $6 60u'c.        or *hich        d*rv
                                                   's                 tud!€dturtElltdEh6*ts@.
                        CONCLUSION
fto to{.nr      srudy   $Md         rh.t mhaEd      *tuE|la
                         in tE bEln hPFC ora* di                    'j'WI'Fqo@ebdhl]|l6-|frdw6
                                                                       hdrqtu6'i.d4c6         dtubr@;a
lhpo6lvo          in    inpoing      EPS tu
iiqeaoo In 'ole efiedtenFs ol som
            he
a3 posrlyn4iic s 1.{h r.c.pro6 b on6 o, 16 haror
@nrbutlns taoiore in rh. p.rhophy3iorooy ot
$hi.ophdii! sd .nh3msd nPFc s-HT m.raboliln In
metre.|dudv€|6idab|h6l
6!b. r1ln hti@ diliy ro{a'd. s.nra        h                           fn€d6d4erhfufueM
sdzochdi. .id ir. .foro!r, n€ l&h. ru.oEr
                                   '?edoE

nurdcsu'kll.djuncr Io dip.rtr'o'b
or h.d3 cEihed ro have s dediciill elr&r                s   menLl     |dFlddt4rtsh'j&i'rdf|lt,&d?@q.3ll
haarih hay be userul

Ack.owr.ds.mod: lrE au$o6 rc
Pardsn scronc. Foddid (PsFl                    dd Linredy      or
                                                                    tgdF.'rsd'$|'B'll,h[Md
                        RETERENCF.S


  Ml|ryp@h,adbtrlydqii!hJndlsa'pq|
, $idri F 6id           cF,   ei I !4?ec.:i i reuda.
                                                                      srys,dkde|]s|nj@n$
               __L



                     rllefu^'^dqd*&<-*'e*
?l.sd,rF.fuH         htudtd.,rbqd6ds.r.!r.dod,fr
                     @'@!ah@gs''.!{r3e'.11471


                     |nfuh.e.tFdd|nIryfu&.oocgz
 SEROTONINA RECEPTOR ACOMSM IN TTIE EXPRESSION OF BEEAVIORAL
   DOPAMTNERGIC STJPERSENSTTIVITY IN SUDCIIRONIC EALOPERIDOL
                        TREATED IIATS
                         r^RH^T        almo!.   AND   D^RA(
                        .VE|e4Eq6dBl4hhk,!,.uaP,ffi
                       u@F.4 oJ 3&e4rq hw,D dx*dh ladh, r21o pdLt;r

    Tr.dad!'t@1i'n'dd)r}flh
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bfun      DA,Dr       s.Hrj^ rcedm lko rcpond by                        rdmiikunioio'&oH.DPATiiqd|uloFido|
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Hitrds   iid (irprn .k 09q) Rcpod.bdy h!v. rte
r.t&! d!          &6iry d       D2   lcebB (wrddbds ,             dr,


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h!dhv6'cliqwrond6ifl.d
rdni.irdio or! tisi e o.iror.rid 6 fmd b                                1,.   dr,6 wu    rib b   dd Kdi uotuv     ud
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  d@flh!3'isskby3.oH.DPArh6.nt''.!'h
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                                                                                  ^r(res).
  AF*dladicdy4iqn'rdl4'ryr/.,ry'.(4
                                                    Hr6   DJ. s|it 2s, sidiqui s, Bdd r ud Hdh
 sPftfuyPMa004)'GQr.yorsoBldNg                        MA (20d!). PE 8d !c6yn4ri. BFnF b r1r,
 ne'Hr]^le@''.e@}@b{ftd"'                             [phrr'yrpiFdn.) for'whs rdrdbn                     ro   $s ii
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                                                    Him DJ, tur n k6! M, 16r N, ari q st zs
  Phfuogde!fi16o*ormvtlj@de                           d Ms M^ 12@61. oirr€6 h e tu o.
  6obincd6r'eD/hb[JrlT'4d@:                           No'oico|!'d.|o4i!oidMtr9ein'd
  6@6 yd tpid &d .tpior aHridj
  diF tuis ,.^,,i&4r Pbd@ &2): ror.                   ffiprlhid tudioB ii d /lal &i ed4 a{9r:
                  s d h6 DJ (2Ot).                                    NH Ce' F,'l:ll6d or
                   h.r,ryid dtirs of r{r-            di|tsj^'t..,.d4F6'rgollgfo|bvi4
  MPMyD rjFdE h
                   'r. rtsP, | ('} 5Gr6.
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                                                     idd|m|of[|bFido|
                                                     Prt re.tud 8id P*tdr.,2n \a5451.
  Nddhduddfipymbcr6o|d'piq|                                          EdH.laM(200.).
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B*hd M. Kqr A Cran ( d Kdrai sx (1007).              'k|h!ji6ori:|@fuhddokl'P4
                                                     fu|rq'rrqfuryd3idPs^@'rr:n2\
  compdiv.i.u*h6'jd].h[3d@ntdrllh
                      or vri6l id qiol              Hien DJ, Sbd N &d hkln M^ (er. Rlalsr or
  mumhrri( inpridis ii brdiv. dy*ian. rdb             iiro$rtdor-id!..d        dr|t,@idd s14rift                  b,
caey DE (r90. N.uorcric drus,iidG.! drtu
                                                    Hhb   PB   oeo).   r! .Fd          or   turc4i 4ia            m
 shEqh@b     toafi^ .Qr: t@r2a.                      uagidorlid!.rn .rbk!'y. r,u s| ,7: r60e!6r5.
tuq DE (rger). s.d$tsic d dormra3ro.f.d'            Hidr RE, Kirr*hl rcoeq). srindnho.rmra
  ofrc!rclt'iehdld.xinpymuilqidrehdli
  fuihunfPdn'h,?y,@,4r'dolo9'f|sJl.
c*q   DE   0eq).   Moro'   lid nsbr !p(r   or &u6
                                                    N!8. o sd    cc         c (re7).                 h           d
                                                                         ^dsrcq 'tury
                                                      p,dd'ioior*hiaphrcntdi!q&E,!/rol
chlkbnsi cr d Mdra Lr (r9e!). Rd.Ed of
                                                    Hlbn o ud    cld        c oeet cry4ri@d ud nOs
 nodbr by &ryd6{,21di,i.pb!rhnho) dE i                iddhPid     h    6!           or$ri4$si. rFhn
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 ^)B.dan45|4@ktm.olaEJ'|a:399402'                                                  R!tuG! Oeq) E6iql
  ed&^     n   .ptu.3.in   d   th.4e {t t detdoranut r,$an,
  rrrib!. T, r(lei r. MGJIa & Md!.r s d                 r6H-@^r, L d@ t Fd'dj.M               e
     Kord r(r9'r). Elrdof l.'&Et s!hrr                 J Pb,&l.. trr:19tP.
     $rnde o. doFiE D2 lqE r,ldE d b Pii|e Eri( (o* rv d xd.F r,|s (,00r !'n6
     f'.lorqidof h nr *iah E4 r Phatn.                  or w^Y rm6r5 h r'iElr.dlh&ci cdB i
                                                        rHr d.rr*i ddr I Eh 14 d c tu;      ;!
  Hnr$ J &d M.rra Hy ( tr99. r(')'raH.Dp^r. r           mra d.9.n ac J , ,rs!r.39a: l.r-ra?.
     turi(l^)              .!d6! rodidld g.t P'is E , l(hm Ms .{ K.d. w o999I liBrdG
                   '!..rbr
     xtnid+indB.d d.FiE                                !.tE Mhti. rd ffiq ri.d i4a.ti.-r
     den,J Prd'@r r!r. rr.i.l9tor2?r-ra                ptmi&t.m@, pr.^o.r'@4 ra{t): 2c?9_
  rtrdli Rv, cdb L !d $r!^ R o9'tt t_ot{. s{rdN'l&lPdH.laoJfi0g'INlfu
     Dr^r. . ddn mii{          ,E er.. Firi !r.*       craiol qi tdsto.i fiq of t{{.DtAT
     hr0'did(*idu6d *r.rr t, ds o n |*                 rlrreill dFdE b Edn ,E h *.
     rdd mdiu d &.'|L rr.rd|'*d;                       Pi,lnr &r, rr(2): r7!r0.
     Mrt{t: t!flr.                                   sdrr r nd Ptd' H o9art scthr. tetud
  b iM -d Mds sR eetl .ty.r.d@b3                       Md|&dd!,lJl\t@r'.2:ltl{05'
     ffi dsbphir J., 4,fir',r/r' t9(2): $16 LM rd P.ollrr Sl oe6t Dit*sdd dnd or
 (e JM (r9e6) Sch,e&Er ,h, &rr J rna_ !!:              'xy6!'ty,hif[E|EdEd!.m6.s-HI
                                                       fud'd|lE,'qMd,/ah&bl:
 Krffi M, Pri!6 E .id ed( w lt9'6r tut ort r,icr.6.* Mq Fd' c !d F,-d rR or'.l rr.
    lnh F.n6 ii $. .litiv .f 6ird *nt^                 ridffi of duF of r+c, Mi d
    !?@ sMor.dE D, '..e.a un dr- b                     .rdddEti. Gd..r b r{rca2{c+
    J. Pb?ftd, tt4t-21.1ty.
                                                       rirbE) h[B n' d'. d Er'. r rbd
 K.F s.rd bi{h o 0ee6t s*h do$i* vdE|3,|!!&f.L6edT'i+HJ
    hct*dfufub$|4toi./4J                               (rerr ricd 53i' r 6 dlp-iEti id
                            ..+' si*
    Jl'lfuiGb'td.fuild&EIi*..|ct. i6il; k&s-a ML {re5), s@tir ffitn b
                                                       fu}'s6lcdc'k'.y
    hdncidFn.iild'&4n.a.?.!lFl]:
 L@ G .i B.dM x o9'4. r4fi-Dr^r, I r|'r-
                                                     wrr.b't ML, s.rh rt vrr!..{rc sc od r|5!
                                                       s clbrl DoFrr D, E.!6. cEE ri .
    |^|ldId'ien{|'|rru,cId                                              u'rdg! nh.r h&! or
   ffi        bdoFidoHldd dIFy              h' ;                             c|i'd|.'fd'e''
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M.!e HY, Li 2, K!r.d. y rn bt u I (20rr               6rvr4rr .ft.! or aj/d6ry2<4|.'@tmiD)
   gd.b' tr iq6: ei, r.y dr. h e.r b rEi              dh (t-or{.Dr^D imn* & ,/ , d,
   siI9sEi'4fuaP4rn,,.d^.o]ed'
                                                     Yr.idr J. $!ris y 8d Hoa.ro K lr',9r Tr.
Millo Mr. DdcrE .d Gord 099t), s.&itr                 ai&E fa r,l iitdtur otft rHru r...o.r t
   {5-nr-2c)          ^ diarr iihibir &raiD (D^)
                                  ^                   5+n t'dqD lndEd i! n-. !y ltrbiE J4
   8d NardmdjE 0r^), hd d r.t{r D18. b rt
              '!.ero..
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Mrrrr. MJ 00ml hr*rlt $! tM                       oa
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  .Ptw.L & e, h.tt.29t41): rtl.|jt.     'r..9&.r,
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   (I05)- rffir      fd,ri..rt!iir . citi.d nvrr
   dr dwbo' ." ir.d.iim df rd6 or
   diFydbdc &{l l/.r. ,o.&4,, r|:7sl0,r_
lL.'16 PI- sril MJ, (dL M.!d lLd D, (199a).
   Ahdi6 .f dr.'r n' tu J.rf,^a+{rr |tdir
 roudr of osic.id AFrisi   s.i!rc   vot, ?. Na   L   a!9 -    2(16                                  tssN: tst.-sos5



               INCREASB IN SEROTONIN.TA RECEPMR RESPONSIVENESS
                     FOLI,OWING HALOPERIDOL WITIIDRAWAL

                               FIid B& !dO'hkkidJ!h..rr&b.m
                 . E{un Shimrr. Artu ftri,
                 'Pltllllertll
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                                    rdonuiq G)nphr, (.mhi ?ttr,. t t irbi
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                                                     AESTR^CT

 h ri.r !r I or. olttyl,|!;rrloni* (*erin: t.|{DlA @p.s ii rtr .tftidio. or crhprDiitd jtnpdr
          Feir
 (EPs), rlE      r'idy ra ddiri.d o mDir 0c- ul po.r'q.E dFrs b ! *teri€ j.ln-r^ l$;d, &
 hyrrd)lz- (dir-F!pyhm,o) rdrtir (0-oH-DpaD rd|*ii! rijtt inc E9s4d (s riE r d!, rd 9 d!F)
 ddh4nrh d broPidot 6 q4r) h re Tr. ir(Biry or rHr rrldffi .ricir.d by 8_oH.Dp T (o5 trr^lr
    Er.n d ma@ d po.eynrdt cF*. 3.oH.DP^T ,ndc.d r,c'E ofs,HT mbbotnn h * ,hem rd
 '!
 irFtud.rotr trE rMrhr h irloFiLl                    ktii. irjc'at   nh.   rr d..@ *E d           ohi.nrd rdt@ii3
                                            'l'{
dfr'hsiibiEd oh!!,hDrc r.rck orlrr
Dt^r iisincrnry d..f*d r.|rr ft     'Euroli$ h 0x r tu NE||siirhcbft ^dniri,Fxi*o.iori.
                                                            m or EFrraj tutim i,id.d uimt
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                                  |eklit{dii'fEgIdt$fo[i




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:r,Fy:r i' ,E*r"ak-lrlt     JR.B    .
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:1]101"111h*D].p]ui.DcIi.l
niE ffi     .Dnr9 6 Drar dE dlsJ'nE Nph k oa
                                                                          eru rn E i.[,ir
(FMrM'rr, ry/rr d ri. rhit'r, rodiq * rrr hio E{h h d.Snh. Nfloi $rcdr,irMry. Tlrr@.
r mry um|l8 d Lgd b dlr,rniE @Dk (s6Nr. rl^,ix dyrr.iEir ft, Er,rrir Lr. d@fr,;o(&Fr
                     'h.       ic tr ui\t tr * ,n E rnrum t.rj,ns b rhr i(td wrNr ot lbnm;
                                    *J|ixth.h|d|iJtlc
:i:rjT.":.i?:1.            _+p"tdrc,rriir,         ru,rr      Nprw rE d5,nllonui in ri..trurosy;r&ircdmiJ
                                                              Jdd 6(.r.urotrurEris. n.o.,.trr.r^@;* i,
lyr6:
       M !,JF. rs'r,. rr     is betr q,aEi                                                ^
D,oFnod
xd ,o'rl.
                    dryuNyrr'oytN'ic *,,1 (Dop^c)
              'M6 rid ,Hv^)                      Mpb e up ,!{u!l|?tt h p6i,D;n
                          db'          crdie rr:; o"*i.; ,i. zoor ri,,",r .Ji* &h,zontrMic
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                                                                                       Krrhi.rrr).                  ".di.;l

;11.tr11,*,f*[ruJ1T;irhrliw'cd R.ati c. q
                                                                           pcsrR Lrbo.Jdia cmprd. K.tuii.7,]n,.
                                                                      s.OlrDP^t. ldtrcd ho,rctroi
          3-OH.oPAliid,*!       Forcpiv tr    din!




                                                           t*
                                                            d




            !   OH   DrATndft'l Frr sodY P6tuE




          @don       for         *dnl cdds
                           tHr ai( ii   th.                       fu@n|{udykft.alofd6ig'1.i6e'iofu.
                                                                  itrkiiLrv oa 3OH'DP !iidu..{t 5HI tvidtuE d
Murd|)h

d-ddnrc' or tm muom m/ or PdGvirPrk .irs
                                         (v'4'                    d-*; or s.Hr md"blk. m,h*
d"r. rcs5). A |[h lrohorJHT


kk " (s:oH DPAI).hbB tHT r                                        Di^r oi ri. o,k. h".r' r ,hc -!.d.d Mn'^ri'i
k rhi< rM ri. i.M .nLli'l( (Hronh d d                     rvb:l
                                                                  ,udr. .n*h oi &oH.oP^r *E n
oH.DP^Trtrdrcdd.!fI$ol'tJT9|h.jt|h.E|ot                           $tJr:!! r'on Er.JL.d n$ itus ! dq br v srrl
                                                                                            D2   r{tior'   vNrn nrY
L,,, H"r-, -d                                                              iit,rc€
i irlrr     or tuqairoric      tHT rA   E(lor        Dv   FUH'
                                                                  ^ir0k.       dls$   or s OH DP T.
                                                                  muochcnicd
D]-A|..rhjFDdNl,3,idFmcLhJnsl.i*]
tt: Hrend';/.2002b, Ni *r ft Khf 20m)
 Fi&?: 8.OH'oP^T (0.5         n'!il!l   crrirdr hyFTrieiry rylddd (f(rrw raiiig. l'rFdfto'xioi dii tu body
 poluc) ir re rcrEJrcily      (s   rims.     dry rd e diFr virh turdFid.r {5 dr4o. s.orl.DP r %s iij.c'dr ?. t {ncr
                                              ddrr id*rior vul€        mi t s.D. (ror tdiil lIrid' or 4l' I ni'
 dunlis}'siglifistr|dl.f.rci$rb,U.b''.'d,''                           'E

                                                                           *R i'idrd   wnr'   #rin' i.   6rre\   or |
                                                                                                                        'n43
                                                                 'nink
ta.lly brci mlg rrhi@ wkr db wigiii! ?20250!
puErLKr fm H@ii E rr,in Jmt 0{E ) R.sEh                          A. 8.lprio.d et r rafid@tid Atu .! &-OH-DPAT itl
                                                                 d{oto"i,E nact nndd alkiop..itot
iidi,idulr rflr.r r   r2 h   rior d,r cr.h (ri!      rd d6:m     Trt .iimk we iqed *iri elie (0.9* Nrcl) or
h) in quib   mm yirr'   fE 16l          oI   edn'r               h.rororidol d r dG or 5ru& itr r h.
                                                      '.d. dia   30 niNB dr ininl. rc iijr4.l wih &or]-Dp^r ! r
                                                                 de ol 0.t i{/l(8, 5-1lI syinom v6 @riro.ui lor 20
                                                                 niruu. Aiiok darior.d
Hrroo.d'r.r  (s6@: s.j q us^). 9!da:i $                          injcno*, 6tuG mv.d quichy rM            lkulr *t
inj4bbr. m,forh, or r I'l/nr. vlr iijc'.d hrn-                                                       'rr
                                                                 disr.d inb ditun .id bdii. Tlc -npb3 rm to'ul
F'irourrr rr r d* of t nuis dr silhi. r-oH-oP^r                  a r0 t .6 muEh.nkd rrr}|! by hiih Fiffie
HBi !!rha*d rM Re4h Bi6i6c (Ror. US^),                           lr{rid crodotftPhy
ra dksk.d h nri€ .id iij€r.! iiroF ds r d !                      (H.L.nlid Prrei, r9!4i HPLC-EC).
dN oI 0., ru^t !. lilol.m bod, rdgr , C6hr
                                                                         3*


                                               Hik4ri!|.

                                                     srjftn rid tnh olslirc prls s.orrDfAT o.t nla3) rd                      I'rLop.idol(5
  ii:^d   i,ld    s oH DPAT         rj€rd      ms. vtrrus d iE         Dlrrce.B by rs
                                                                   '1s.D.

B Mhahrtt oht h\rb.tdt<nt tfilt aI s ott Dt'l1 h                          8.OH.DcAI .tititdt s-Hl         vrtQr.:
   htbvi\ tqtddt intutio' aJ hdor{idat
'!tr                                              16lgfut6.ArNrii           Plnplx sriy    ry   us$   (26 r 26 r 2d) w rr'   lLwdsL{vc,td
or rcn sro4       Nln                   wi'i                                r@' 15 I h.rod i"luri's               \LLrim     d 3oH-DPAf
                'tdt,r
5ng^!hvol]ft\dl]ry|olqdlysb.                                                Foqh" f.xditrg ,d l&orotrdi drL.
{r! iin{im) md:r0rr3:30 pn. (2"                     itrjcdiotr). contu      vucsornrsds.ib.'rorrs{Hr&ii.!u9?).srliLE                         d
r, N s wlr ilqtdvrd,$rir. I Nl/k                                            LriLq,.ridor   pri,jds! rr drd f          5

LiF* v    $   rd, ! ,      rii r {eE i ,ico"d vi'h Mbpn doL o t           quo nnL          ijcdcd
dn di dry.li6                 rrLd lLi. sr i,i?crioi or tu M or                                         s.oinr Erio'r (5-15 0,h         Poil
                                                                            iricdi0i) wN dlrdd         M
                      .E i'i..td *ir i.
oN.DPATdxddq.o|olns/|gco(rc|M8i!oi
                               ij.dcd wili $lirc. 5+rr rytrdofl.

dc(pinrd      L   hr   r   Ls th!   u   nc o, $   oA DP^r itri.d o B        trwt i         rorupN


                                                   {icrc (rrir.oiMd
 F34E|icLof$OHDPAT{05ng/tg)oirh.{n{rrr bi'i5.}l
 (.Lj ue\                                       d tr rnlrs br                         L-rc{   Es. rp<0.05   I   3.(J .DPAT
            ^riildrc!rK

Fm,f,' fldrph wor hoftgor/d        i                          Dirlor   rs ii   rhc   iRt6{y or   roEpnw rrcld    rg, l{Uody
                                       ri,jis ots sdi!   tr                                            rdlf h olc lliol
                                                                                      w.rcddi]lkll],'slcdu!MuF
T!fu[o'logo'alJd|'ghsFldohfuFJ'd$!:nbA]                       whiricy r 16r. Ncumhcmic, drb or 6c(n!4sof3-oH.
Fflo6ry tHl cf'.   Lett)                                      DPAT on m! ndlborisr. of 5 HT qc
                                                              tridLbl'P<0lwrccoNid.Ensisni|'gu.

 ^J!oose|hn|iolcolunn0flfiniitd2'0di
rcrsd' w* u(d rlc nobih phr* lomris.n of N ud
                                                              Filur I irows            s,HI synd@ rfotrrd*
                                                                                rhc inEmny or
(rl*). oss (0.r)?1*) d EDTA (0.00354J ii 0 rM
!l'G',I'i.blrrorPH2'9'5pud                                                                   FrE) .lirircd ht
                                                              0.5 ng^e &ots-oP r h ob pEiij
i osbn now Dk (rnr/oin) rnd o!.Erins p!$ur ut                 h||oFn&l(5.0 ng^s) orb ir!rr:.d by Mlii-whirnrt
                                                              (pd05) .nd hyp.deomoion (p<o.01) vcE wlhl ii
scrriiurLu lEcD.6A ddedor   I   ro o
                                                              hirop.ridor rh(r mrlie pEirj.cred mh. &oH.oPAT
                                                              .rrciLcd nd body pck€ (p>0 0t ranorrigiifiod.
                                                       a

                                                        9,,




 Fi!.5 ErTsB or 3.OH.oPAT (0.5 ndks) oi 6c n.nul                                                     |erld rtrLo|l.,idor(t
 *irts f. .) dut i"j".rd .". v',r*"..      rso  ft*         s1rth r ditcrmr        by   !E* r".'p<,.rrs r    3-oH DPAT
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                                                                      pDii,ror Biol             PslcL,i{ ?7(4J ar5       51

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                               A reprint from the
Journal of the College of Physicians and
             Surgeons Pakistan (JCpSp)

Vol. 12. No. 10 (Ocrober,2002l pp:588-592



DOPAMINE / SEROTONIN METABOLTTE
RAllO AND EXTRAPYRAMIDAL
EFFECTS OF        CLOZAI'INE IN RATS
By

oaraknsh.n J. Hat6em, Farhat Eatoot, Nida H. Kh.n, Noor
Kamil, Obaid Ali, Z.rar S. Saify and M. A. Hal66m
Deparrmenr oi S ochsmltry




Prcf. Dr. Darakhshan Jabeen Halsbm
Departnent ot Biochemistry
ORIGINAI     ART     CIE

DOPAMIh{F/SEROTONIN METABOLITE RATIO AND
EXTI{APYI1..AMIDAt IFFECTS OF CI-OZAItNI nN R"{TS
Damkhshai J. Haleem, Fadal Baroo , Nadia H, Khan, N@r Xahil, Oba d All,                    zrar   S.Sairy   a,t   Jrr.A.Halson



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     orrLgry    In   rh. Er   td"/r,rffitl930i       14e:   r7t3.   37. Hdson      PM SamrCS,Ocena MT Cuuoi G                 dar

                                                                       ,rph. do&r1.. l&dsrr?1939i         100: 276.30


23.9a*e K Gosd M, Xibines H                                            .ynll* ls g6.lcr rn leml. rh.n *                  db   d b
                        pEsynrp                  t   turoE.Prod        ioa tuEg. by !b eHrrA .lo.ld                      s4HoPAr'
    hll|d8,1939'@:3g.9s9
29. Ms@,i NB oad'.!lC semad c
                                                                       phrcirrh:soonFE Klph             DJ,   {.!i). P8v*rcp".m*


                                             hL v,6srAsb.                                             n.lqrc .q.nB on
                                                                        ,,rrdr.ndotrndu.d c.br.p.y rdst 1930r d: r 6001 5
                                                                    IPm$enEPxb!6nMs.Xo6kwI
     &rndftralrrd flwMd 1ss1t t'a                230 3
                                                                        Bu'ot'l|crlid'HtrAuq,nd.hpl6hle|bh|v.
rr   asa{ c. KdG r. Ho and v Rl                                         bd1hod.6'ol.niDsM|c.ndofuryEn.d.|
     Atr.idioio'hlotsi&L'fuqd.dbprl5Y.'Hn                              e*Rrliqa&drylg6|1420.6'
                                                                     4:.s'rEtu s, Lr.bem J, Porr&k s saneM                      A
                                                                        Mun€F.'|dc|qplmd*td|@cnr

                                                                        nndlns.. Sirt Prttptty lssst t7: 52.5
      ph'enlc pdionG r4ly:/t/,72000i 15: 333 e0
33 Bdh w'       ap.l    B, Bldd HR   Elleb
      ndrHtu d sbbntn.n d bdn Ar"rdimrre                                rdB .bdn. .i[4r                 : nPno&n         6e6d


      r. t;.^tn.        h   $.6tb5h          tuet'tbtb6"as1e761
                                                                         ni        tudt   arhFetl,r3t   50:   ffi-dtt-
 s    slmd Pw. c|!n ce Nk€oYd s
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      *otonhrA.zA|nd2ccc'pt'g.fue^p@'on




  t€t                                                                                                          H,h llll0lllilll
                                                                                                     'Eflf
 P'IfuM4Pfudfufu

         NEURoCf, EMICAL EFFECTS OF &EyDROXy-2_di-!-
           PROP)'I.AMINO TETRATIN IN RATS TR.EATED
                      WITE EAIOPERIDOL
      ERUM SIIIRIENI QURII^T'UI?AIN TAXtrAT B,{ToOL ZS.
                                                        SAIFYT
                     Ai\D DA-RAKS6E,{N J. EALEEM
               DeplM d Btehra\. tuq 4deu tu Bt^ k^M
              tuortutud.at,Md Lddq tJ.iEd,o aI^M.t
              .D.paad ot ptttwdta ch^atl us*lD;J K6da
                               Kdetnrrttl4 Pottitu

    h yio or: !6rbL Eh of lByi$rh .en d rrdo,yfy!.miiq 5.nr)
    R.pihnkp€:libiolof.ePym
    6Bid 6.nEhsr. d. m@.tunhd lfls ofr *kdk rmr^ L,.nd. t
    hydoa-2- tdrFFlgytmim) bmt r {roH.Dp^D ii nr fo.tdwiig ring (lriag
                            ldlyfu9dly'dd63.d!54i}€|[sF|do|


    5.mdd ib n.b!.tir rrrdroryindot*
    ri. hi. A, inis irjeri n,'rl hftridor
                                     d !r.d ,hn Ina d. rd ,ijerioi or
    hnitr cooYlet, dirryitunhay,l& &r' (Dopac), ft e rdtotjb or D^,
    diid!do'dcb.ji'^d!!i!il!llido'loH.DP^r3i'nfia.d,d.c*n'rrT
    Er.d di! hj4! c coo.Eri l.ft de df r_oa-Dp^,r iijdd ro
    Epadry doFido itdd uink did
    .F or r.oH-DrAr inndidr dd!rc
    h &eddry $ri. ij..Ed Minrr! d
        '



    6*E.psmyEhw|F-diil|xlr&ipiliiooorEPsobrcft:diip|ii!d'oi

                                INTRODUCTION
     Pl'thdics/n'obmi!did.di.lr98ycinli.digd6fdtdbyroDl.,ti.dfu!,
E N d U6i.lr,200r; Robur FoM .!d Xuia 2COrI rte &uss .@ pDrood !.drid
Md .hen:i pddry a ir d,. oidt hd len eiud {paEq 2m0} Evid@ r\{
mlmhFn ddg3 h.v. onfu{ rbirit 6 bh.k dE doFrii. @1) @b L hG.d .irid o
l|Fi diit ofinhibirins D ninuhed rna,yle.rtl& dtyily (Mill4 r9.) d itr diqlxjq
ir'c r'i3i fiiiry *'d;,g df risd b     D @d (sm4 te75t                  Mbhcriq
                                                                ^ 'ytdt
hlropdidor jr 1 D^ Ecrw $bsdi, 'h. d. hh.m ot psiriv. s,'pMs of shiadftnh
                                   fo'
(Per, r99t. Tni. drog l$ i |tish !fiiriv 00t6) for brclrd. of D^ tr? epror lid ri
rrp'Eirbl. itrriry ftr bbcrrde dr DA D-l @pior (Hytul,   1935i   Huky,   1996r   Mmshptr,
                                ti*atdEd qbB 4 3-b,&qr-ti-tPwltu redk

re99r Ir hBEFri [d rr.roFidor i@6 diDdoiyrh.it&nc &id (DoPAc) 8d
              b.n
        rid GIVA) 6d-t of rl. @dN+pumn, ck6 ecunbos rd n.dirl
honovfilric
rE $d.otu (a'd!6ctr d Kirpdcrr rrq)du.b o ii.u. h D bruwrednrhgtu

     Hr            sErto wi.t r hisi li.idffi or bt @Jrydr rvfrPtdr
          o(ndor rhdry B
rgls, lldr! P'kroikr, rM dlrrk4 etr d}lbir rB|lE 4d hi'!. reol) sd
d r dnkdh Gd\ !4 rqj. b

n;n Li.ir'. b d! 'ffi.d dpr or$rcmi hvio'(|ffi, r43l: r6M ud Mu&L
rett: J'i. r,ieo) Ere.irllduroidd* rB6B tu 6d d.flmio4n urMiri'n L
nrdY d. o iE udt 4 0r D^ E.
.d.irb" h sc!rd.'.k-si             i-.Nd orFddb'nFtM hdi n vth or
rid horor bdNie (Mirtn, i{0ol tudr du qt.r rld lvtrr Gldlcp'ie shw ft*r
!@nhid.l lynDtom! dd b ih. sdd dodl|jion ol eobi.tr:ic avtu (Ninm !d

     I' ir w. I dodn.ftd $d     sobih      (5   Fl   n.dhB . wid. nG. o' phy3iolqisr turt'bn
;".d br.! h d{i dhobed ad FFqiFiob8'or dditioB tmrA EPro' m
,.i.kd * "i"hg "f "|'i""Ph-
        '
      @E.dslr *tr pl*F.tl
ti;* id'^"Lb;. Dt?, "Aeii&;o orrcH-DP^r rd Lmri.b.ro *rr iMh'|in
"*d                                            d@*
;;:; d..d';hi- oro@!."ttgidol ((-. tu b rt02) I D^ si'
                         .FrrA
                                                      iB Er
                                                              ssEH
ii ioiiiiiii Jut' ;-ia;        '!ccrr.', dvlii'tr
                                    "..d ry'hn            orl{H DP^r
i--J ruiol". ir"r L*                 tu
                                      'u;,to".n 'd^"!nd-
l;::d;dr,r.
gll*:*;n m.*,:l :':l;"liH,lf.:,:i# l il;;f,i:;#Ddmdd
                                               $*l3r
lii*':'iiii";i;.r..mq         5n/m nd Ed"'d
                               "s'id;$ix
."ii,i ii.iil", ;,yp,*t e'6PYn
     pd'.rry.:h   i.qo
                         ..";t.pi
d;                  hLB


     rd Jnd.ddd !   {   . or   tHl   rA   eP.d6      in rhr   pG   p   dior   oJ EF6'   br   prM rdJ u
                                                                 nodll*
,-''.li i'i"'i.'ii"i "r,"r'. ' *t ";EFbd in'^irnuoi r! bs K'd@!i6nP'i"g       or h'ro'aidor
,"iiii;i,ii," ii"iiiiuJ;;;;" s'tri ivi'tsii nob'rism ud ds q DA n'6'i5
                                             rhtr
                                                  'trd
                                                              b'
il &.ii iiionop^r ' . a* "t. im!^s d.' 'Hre d.v')
                                       d
iii,l,l'i-ro:ii* ir;a;;    .r'a,*h;;      to                         d
                                                                         'd'"i"i'd- "rh'hgd              '
                                MAfiRIAII            rJ{D METI{OD




ffit":ff+sm'ltP*:mr*'i*l*,-"xm
   Hlror.ndot
              'srqE) ^!l$h 5i*/nrxs
                          h                     m4b vs rd.d hhFnM.,ll) (i.p.)
&ox.DPAT Ft!!!.d tEh Br cbd,ialr             disd i! rtft r0.!.r Nlct n : dc. ot 0 5
n/mll€ qrd     i {. ffi'     ad h.   m


                                        .* N{ ) or rtloFidot j r dG of l[!/r3 m r
b:I'..d &gD             ]0 mildE d| xjmL N4 inldcd yiti loH'o|^T , I d... of o 5
ne*3   d         ^id
           r-oI{.DP^tiDjdc .id darpird I tu rn{ lofl-Dp^r itrjd.c. Bnto
ft@E{    qui.kry            !ft di$ccd tnb dtu&n 8d Br df$. bnin. Th. sph,
                   tro' .h!.tu
    dord i -70 "c fs rcloch.mhd lirtsis by hish p.]f&Iffi tiquid ohmegEphy wiri
'.6
ddod.nisr d.tu'ioi (Hrl6 nd Pmd, ree4; t(el a 4 200t: HpLc.Ec).
&  r{o.r'mior .'rs.r r4d-Dr^r m n3 tdh4 qsed iojdm d hbFndol:
hd@lddorr. dc.orr4^s !o            oir fo' e.r)r &sd eo!.r l0 rn (r. rrc'ior)
                              'in4
rd l:00rr0 pm. o- hjdioi i. cosh
d'r r d6o xr'a r6i rinrb s4 hr@ hib b.rop'ier oi e rod oy, xiE md h d
hjdq of dnE d r.r.Fidor, . !o!r of qard !r,n. xd u*r !tup d wd
broFidor irjErd ximlk lE i"j&d fi'h roH-Dp^r .r r &sg. o.0.5 ,s/r.. c.ihl
riinlr of !o'h 6r @F *E :ijdr.r q"r !d'e tu dinir wE dd!'ied I h d ri.
sh. oi r-oH.DPAr i,t&rior
d.sib.n.&. .G(H.15&dP:t14rr91;IMt"/,2000.


ryltn ws h.6md04%), eql edni rlphn!               (oss, 0.214)     d BDr (0.05%) h 0.1M
Dho'fuebof..JofpH!'9'E|ebi!
op.diis pob'i:r of0.I v    Gle   c.rh.i   d.!!!e vi              elc.|a!!d.t
                                                          ^y&c
    th! €db    ft pe     d 6,{' !s,
(ANovA). P6rro.     ehetkdi3 !!E dor! by N.rhh.Kluh             d. vlra    drP<o 0r    Td .<0.0l


                                          RESULTS

   ri.,I o* u'.ldd' or tHAA (lA) $n tm rB) in Ed ofii. bsii md srhbrt
                                                      (

           slii. + SOIt-DPAT .nn idop.ddol + 8OH'DPAT i{.ot d tu. serkft'l
rnAA (lC) or                                     'tu
adyln by @dhd *n Evskd th! vdG oftB^A iD rh! didd ofti. M Fupc r+
@ncr,r!l.'Mat2l6of'.rrrxd'HIMiIdFdof0tb:n|14nJ|6i'hdoFid.|
                               irj.d.n tu. DinoEE br !d qlE d:iFirBr
                                   on IHIA^ (2 ) md tm @) r*k h ri. ftn or
Ih. bnin 6d   diad trii^^    (2c) or EFrbdry   slii.      .nd rcp.ftdly ltrlop! dol   iij.d.d
Tfcr.y   ANOVA (df ri   3).lo*td jsiif@r .fidh      of t-oH-DPATor 5.HIAA in                  'd.
                                                                                       !\. nridln
                                      N4nekntql     F4t'.u a! 3. I t   &ry,A

(F{r5.   P<0.0r)   sd ii        cr of'h. bnii (F=r2.r3. P<0 0t. En6b of8.oH.oP^r foi 5,Hr
hv.rr w.E   id           fi.ur in ri! Br olrrr! bnii (F{,90, P<0.05), Enc$orh'rdpldord
                            'h.
                   'is                         i4!n(r=[3.57,P<0.0r)btrior      irh!E   orlEbFir
(F.0.03. Pr0,0J).   tnkdjoi bN6                hd
5   HrM (F-r9t H.05)        in   ft   nd!tun   rfir c{.3r, P'0.0t dd tm^.{ (F-o..r,    H.ot   h

   Pd'h.cu|$igbyN!hf'K.ukl6
                           nontghniorrcFdcd|y9h!elio|hEFlbdly
iih;d .irr, hrroFidor                             njrdioi dmi ii eind,
hncd *rh drM ud Lru   !rh. o, &oH'DP^r hi6rioi.r1]d ditr.gq d tqr^^
                                  "to'




            J




                                                                   l-:=
             3
             j
                                                                   I
                                                      (lB) hrb itu Br                       ol
    FG t Eff(bof t.oH-DPAr'0lhelg)d 5 HraA(ra) sd tHr iil-td d ii vrruBft
      h6D dd *iel tHsA 0c) ii sLi' iid iioFMd Onsr.g)
    iH + s.D. (i'r) Difi4ns bv @bil'it6'r'E io'




 'ru3[tffi**t1.g"6-..ig*mr'*,5*s*
           i                                  3-
           ,!                                 ,!-



          !-
          Jd



Fi!.?:Er.xGof s.ori.DP r(orEgr{)oi5 r[ a(a)rndl-l]r(21)l*khrhcdotd!
bnri od fid 5.HIM (t) n' E4.d nlii. d npobd uop.,idor (3n ,*. ft. t det
                           I s.D o-1). ss'risn ditr4i6 b _P4.0r.-Pa.0r 1
                                  n ..peiv.      nl&'.d 66.
                                            'rT
rcrabd i.lopsdor inj.*i Gb rffi Eiperiv. Erdd slii. lijd.d E! rdlb'rig rlo wrv




  fil   4 sh@rdreholdii. n.6bo1i$ in rh. s!h!m ,rd li ih! 6r oftir. bdr or@*rd
d ;
  ,.    s.H.DPAr -d *F"rd hlbF dor + 3oH-DPAr nj4ld n6 1\w *!v aNova
                               Oh DPAr r0r ms&J 01.!'m 'r'26339 P40r)
;o;d6. b,''; {F,q., Pont DoP^c rd rd.iglfidr.fide t'dll|{ fimr                    r'
DO.O$ d d ofri. htio       (H.a3., b0.0J) D EfidoasOg_DPATY.rcdli3
tu n;r (.=           Fo.0t) rd Gr of e hhh (FLrs, h ot av^. Ef4! orhioFdid
                ror rnrbl DA (f=6n.7J, P<oi r), stubr Hv^ (a't 70J, P4 0t.n! Bt ortr
v.ft silirri€d'.?'1,
..^ doPAc, {o r. P orr !n"
                         o
                          D4G l6r' P'0 0t 0d '6r or         b
                                                         '*
H.orl rd d dfrh. bnin lF2tt. >0.0t) DA, fidd 1r-0.02t F005) &l 6r otdic bnin
(F.o.lj6 Hjt DoP^c d *irel(F-0 e, D0 05) mn dr ofti. bnii (f-2 51b03t
                      dtu d kdmt   w   B al &   dtd. dy   z   4 4 + ry,ytM no k n d t.




        I
        j                              i-

        e-                             J'



H:$tr**:*i{i#f,fl{ir'}ffi liiiffi A'"r*"ffi                                   ,{r;?r




ffi*flitr6[ffi#ur,r'tr*ffi     DISCUSSION

                           "fi $:'&?"*,iiL'iJi;:,"*i?*T: iH'1 ""i
"-l::tl::i:,1i"''r:':lJf
6.Efc.!€gddlh!fmd|(:eDA
(Bodei md Dnnond, r$ri M.llod !' o/, Drst I L gliu.Iy eutud rid r.flr r&ikc               m

                                       iiF (K.llbd ., cr
                                      eeo r b rcLt do.lndrd         dr   DoPrc hd wA      r

            E -",*"*'                           I **'"*,

          i:                                    t-



                                               l-




          3"                                   3'
                                               3-


Fis 4r En*c or &or I DPAr   (0   jntrs)   oi €ktokrni^s ndlbdrLn ii $.       !   rm iid   itr

6. v.tu6 ft 1 s.D. (i.t. sieirdr ditrcErq by Ndn.i Kdrs               B rP<0.0r h r.oH.
DP^r iijd.d tu rM eedis               iid'cd d, +P4.05,               *k0or h EPdd
hl.Eddol iij6r.d   d   rmm       'rrc
                             6Fdiw                  slii. iij.d.d   uB rol|s 4 rGky
                                          'iFrcd
                                  N c'' uh. h b ot    E!tu   o! & Htd, ry24- n-       |'qtt Mh f d dl k

 qu,ririwlyrh.Mrdgiiiturn.bborir6orD .orr[4Dor^ckotuieidlEdbr.!i
 iids of itrhidrml DA aEboliln {wBbrilri l9tJ).
    Ii in.           !!dy,   .ffd      of ii.h hslosidol rdnii;hdoi m * Mt od !6t of rh.
 hdii    6d.hix 4etuirioB rft d mdibri.
            ''!s(                                      sinik rtdi6 tm or h6od Emdn
 'rdiid.h.rorri..|injdioDd,deorsi:4in€e.D^iffiin .d.iebdr
 rnn iibr (Hrrm., d, 20m). sowE, rc fird ihn 5n4 of Epard {2nE.d|r)
 irjdift of iid ome/ro dN of I'jorridor d6E&r D^ 8d Dop^c @@hdor in ri.
 .rldn. r n ilro ior.d rlid !06 D.{ |
                                                     Egjoi'T1'.PEsd@lftsho*'d..ftI.iiDA
  d.6dior n rh. n'inun ot riigl. hd.Fidol + !oH-DP]|T ri6 nliE + I.oH-oP T
  i.jdd oimr!. Tni 6uld ru tE:ir* or i@d EL& d ffihdih or DA b HvA
  fo||o$igh|h9didoldninilHj6'colvBly'aiid*hD^h''16fui&
'tuidn btr ior ii rt. d of rL bnjn of Erlqd slh. + salr.DPAT rd in Ep.d.d
 h,loFiddl   +   IoH.DPAT inilctd nb.

    M'ny'udi6luv.lhwilrne@lnnini3dioiofhr|oP.ddo|pmdu6ided44d6.
 iK.e  in Dot^c (Ke!n sd E3u, let) Id Hv^ G.liMn md F.'!d, 2000) k%k
 *hid & or.Els n'sud     Ltrla drdni h $. drilb (Fryr xd rod, r9lr ) In
                                  '!
 bnb               hior.dd + rc8'DP^r ,hu die + r.oH.DP^'f id@n
         rc; rilhd h     3insr.
                          did mr nodit t-|l DoPAc ddd h rh! $nh d
                          |(L(*.ui, r97) o' rieoiiq i6d, r h4d ddoe
                  + &oH-Dr^r iij*d tu dld @!r bs6. of EFd
 dDhl;sq of i&Etd. tu      {dJ F kf* @Eff bn r€H DP^r d ' &r
                                'ert
 doj4^.drorri,n*'6'bi'qnddddorrtuhho'dH!^                                                tdlnq*d
 gli!. dld 3i4k s rc!.tcd lrl.Fidor irjd.n d
                                                      nodJ   d   rs   h! mrni9   or   doFn. s. (Jom
 'JoiMn,4.|9o:l$\d|l}ts!of@b|b'HIqL'i[.bIh'Pll'goao/'01|) r tr.
 ;mr^ *"" * ""d ;svDtrdv s *r d p'dvirt irrrv M erL b.die
 na\e ** ,8 &ir"dd d;ht tE t
 J; " h-.d .           b"r" * ie. *             d.- rF ro'p.a
                  -v
 drrqfiF nd!liz, ro!!:sp@ud^dqrsdd   '.b@
                                       lo', HrJImndo/ lelt:H@d
 ,r reo1i.. aa too:tir*",r reeo) Ind.D-.'tu) dnh'h'oBorloH'
 oiii a:";         r.m
                       '"a
                               s.m^^ I"
                                         *n
 J.,iii-           i;.rn*,      I" m
           "i,i -,
 a** ,.1n.-, ttt'a a a
 'P^Td4dd'HTEnBgrsij                    r99o,   ft! ldsk rdnlnituon or |lrhFnddl ! | de or
 i;iii-Ii;s-tlt-             . * *".            hs hal *.      DBur' (H'lan dor z0{2r'
                                                          'tnm
                                      do'i'#'dottddFi&|!s'iru,.H|4^
 .-.i'i'*J,.i' t.'n,""' n" ";*6 $.E no, obF.d n s! d ord! bniidftri* ir
                                                                 s nihd'
 i,'ii 'i Jilitir ."i v**r " " ,200 ) *E Epodd hd impdidor {!
 i-"r*"",. ;." -a "**' "t oa h h n'M ^ioi,L " qr 0000) rbd oa
                                                 '            "*
 ii-,. iir*"l.t .4..r*- at -
 iiiiii"rii ii-E*;;; i;, r:tu '.ordo{rnDtu m.ri(DRr4 dhd'nor
 i"ilii"*ii      i;;     or.
                               ",/      :do'i
m.drd.d by rh. 4riv!i6 of D2 riko DA               E d       (Hrj.DriM., 200D. rih cn4 k
         by hrrordid.l (Mirtr4 teer). I it               nron d i'n Eed.d hnoe.'idor ilj€rio
'nbloliad .!n!4
inGlld 6.                             'k
                     otdoaiiali. [, @rG ({iq                l''o.id rffiiit of &F,rE,!j.
Eei6 wnt          |goiin btdi'ts ii d.   hii! (viFr,4 2mD. Ttq ji!€! or'H
                                         i li.,* in d.Dinii. D2 @rd d.ait h 6. &6rr ^i.
fph! (DR).
   n&   lildbs b 6b rid dnhirhrbi or rots,Dp^T ieifiNrty d!|td 5-Hr/\A
hv.k h      *idm o. i!r*d h.loFtd.t lijd.d M id itr dr EFrd !dii. iij.d.n d
6 6! od' brd 3.oH.DF^r, da.n
       'r'.
bnh ot Epad *rft iijd.d eiml
lahFndoLiild.d Rr                                     updr irilit of pBy pri.




                             .mitrlhNddlmi'idq.!fol|*iisEFd
fuIioidiolofi.roF'idolcd.Dl|'
G.!r'on 6tun4 tHr Ere$ i' o6a        is da,!d i! 6 i{ardt njd {irr
                            r ornod eriiv h! bdi shdr h hsy eunia tu
                               'BioB
                                          pb'd.'6dm!c|tnsdor'Frnh{!elud|dyii
                                         Dror   dffii9 u.   bo ,   iiErv.d ii   rr,.   l6b!    rdd!@ or
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                                                .ord.rsi. rdrvity ii th. .!i hipposnps. Arr
    N,votE tuphmL..t r0ls):)t 24.
          fi.L     l<irp&i.rc rc. (1961 llatrdm b, t€H-oPATof hdt dr.'sr ad
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    ir dr      '.d                                                          or
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   eriDrychoiic   n66rprid.: cohpuild vid bm.gmid. rnd doati!. &a J PraM,r
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   Id (3!uH-30r, ditr.mt'rlly rtrd * rdvit, oa nidbd
                    thldn, D J, (200r). B.iflio!.r ,te! or 8.oH.Dp^T in 3insb md
xhm, A , Bibor, F, md
  *rdrd h,lo!.dd.l iijerld nt. Plr,r /Pr-r $r l,qli 9'13
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  6AN. dy.ki..i. |fu. Ctk. Pryhophd mrol. 3{suppl ): s49 5?.
                                 N.vd-lwtrzt EltB       ole,   ryexy2"tt.n Ptu${tuifu t ratk

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    ?ry, qtu w ola a tl t t: 2Lt3.
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                                               od ErEhD6Fo4&ll tudi.r h 6. d
   h'nn.Nory'fun&e.c\lrthPfut3'|312.,13'
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-.#*fk#iifrji#xrr:*li'v",";,:l           $:l!Hs:'*' -                   Fg;fi
P4kbr   hwd olPkm|'tid kn@'


         BEEAYIORAL ETFECTS OT 8-OE-DPAT IN SINGLE
         AND REPE"C.TED EALOPERDOL INJXCTED RATS

     ASMA    KBA\ FAIEAT SATOOL AND DARAXSX.I.N. J. HTLEEM'
         D.ptu d 4 3 t,c b'd' tt N.v dkrnt,sd tiMcl nN qtetua t@l
                 R6a.h L'btddt, uDkdit   otxddi    xdd,i7527t\ Poutu



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                                             roEFw rF"di4 (p<0.0r) ad
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          rb orddr,8-oH-DP t (o.lng&/nr) indei b.rw;drsndm B
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   mdibd
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            'dmjrkhtion
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   a!.d.i id mbi.ri. i@r.!ri6 vjd! m'^ [3d! i' lsdi b jr'rm ri.
   pErt'i€r Fnr. oa i.mrqdu i'd m.r b. or i,'6 ir rh. docroptat or tw
   @nFurds .hd h:Y. tak ft@ri. t

                                INTRODUCTION

   ri.di6qor6a.djn.ft:js
Fds   dE M inFtur lrertubdar     d of ri. ldld blr or d. 20' aery
          nwd{hbilirs d drid.''Mt:F! sld 6 br rh. nd ffi n.dl
^.riFr$oiic                          didic Pdi.. $d rh€ry'
   aLddshadiFychoii. d!,s!   i'r lci wjd.ly Pc'ib.i lbrh.he. oflcrri4Pbirr
dr4 $.       (i.ld4riii. RJ.. l9rl), ri.n ta.fi.hr.ft!6 E @npri.d bv inblunbt
         1950!
moM. di$.d6 lx*l h 1974 dio4d dE urill .no
blvftDlFoq I M{r4'ic c2 tirsoni{                    d rl rol4: Tu td Co.{ r034r k I
Fbr mlornrk !r6hd                        'clMr
                        wiri r iid rqffi or k4 ('nPM'drr id. .tT.* (tuM .
                                    ddr'1990,H&Fido|n@d.d!'}.do'mh.
Rda b|fiiis rshr rd.is cti.fy on tr c\s rad.r a ar' lo70r' Tl'. el'"\'6phrrr.
miod or hrlomndol rs trir b M !w DM                  lhmdhiud 'rd 6cto 'dn3lv
                                                 'nu
                                                                      8.ts,M qtuoI3-tH-Ulf
NEpdd'hddldnglil@hli6orn!6\oxyhtdnlbho]ldordoPnil!in|nil
(cer$' fd Lhdeu rt6t, n! ir*s in do@iE diyiq nly b. rh.d b rh. dlcEs.d
                                           $h a tHr,        ls'yhhoL m (syiid 4 c/. ic74)

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adninilhrion drr)! d.pbr rbBo'i3! li.l3e ri. d.irily ofD?M.lrof (Brd d o/ it97i


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EDro'. fi. tml4 @!rs i: om ol *@l 9p6 of @ir@ f* J+n dd 6kr id bnii
C.d!s. d er, r e3D. Aubndiosiphlc tudiB or d hnii !!ir! Pt{- &oH-DP^r Ercr| r hish
dadt ol5mA biddlis.h6 ii b.d d'. nid bdn, n!h. ikhi & ii edh roE brh qjoG.
5qI^a'b6h*dho|l'p,g,itf(i'll'{'xreIbdi6iodEn9i!@|i}ig.l!
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                                M TENT^I,S           ND METIIOD



                                            in.]lwigld2002503n.
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r.   tubFndd G* ) s        0iLtrb   ritr I ns/nlntdd4      *s nldrd
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     d6..r 0r 4eg b.dY wtr                                                      'ud


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'nd
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                of
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;.,;;|.oH DPAr (0j.*A/.r -d
   artni; lK mftftd b PdF o
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iiddlo'iru[|Yot.ldb10filBFo4qdmgdh'FfiffiiollF
cour.d, Fld b.dy potun w $'d oi 04 sh of.bFi b m-imn iiksirt

                                                                      mrrd
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b Mutr-whi@U                 GL v{c P- o 05, P<onrKt66ied tBtidt st'a
                                                                    iFdd

                                                   RESULTS

                                                      (o'lmsAEn|,dlid}HT4ien.'fd4r*
               riet-*"               -r   n" rav   !dn' ii 'nsk dk* d            broFddo' ri ns^!/mD
'-a.i
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rpdsi-ain"r&"*'r".rso:ottwnhd'qi n$rrdl   mroF6r$s''iepriixEdrd
FH-DP^T dErkd ll,u bodv tdn (P'0 05) rR d

                                                    |orm,lq,ll).|Eed'rfilFdffiiaf4F
                                           n; u,.v p"n" i";Fd '{* -d 'l-'d r"'"F"el
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               * *i*" '..'*.. "rk drftMr or b'c* ldt r"h'6d'r !n
-"ifrir"iliiirc'onr * ; ,i!.irdrv r;'a!dv
                                          h rF
                                                  dn!("o 0'
                                                              d
i--i"i"ii ;
                                                   DISCUSSION

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 ,"; ;;;"fi;;.;. *"". ** rdE idl"d r db bhar hn r@
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                         rc?e.
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i ;; 'b hhrry or rdF.     dri. & t'Fr*d'on tr hih h
g,,l i".J,1..      u':.4" *;ioi;i -"-k/B h*c eF"h'4r" R'om
fi s;d&r-kd ryi0rk 6ka.orDA (s(m- res)
    6dr,. rewstioror qlqb'        !eoii3' rdrBd'(]dh otD'dncOrd
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                                       R!FERENCrJ
e,    Nl., sudF,    s., coNdL H.,     Flq    K.   d   u'B4r.d! u. 0em). R€.re diyi'y &i
                                             ! dbr munr.rriG   ,u. I Ptrr6or. lr: r0r.rr4
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     &,si.d.hdg.   att i Ptuo t!r:153.16l
kiq   M.8., Cci , c.. l(o.r, w. 0997).   tlnr^ EP'.r.eid FFni6 of d'. ,riFrhdic
                                            dd. sd'toalk Ev r Ptnntut 33112'3, 141'

                                         Iofp-toh(.nod.F               ln   c'h'n^C cn        dmD Ls.
     tulrrw. Mldi      , E6. (le3t.      th Phmurqqr 3eorft
     M*rri[& Pubri$nt c..    !r.39t'41?.
                                         ,1., Joah,    v H. virli.ll.       s.N   DdGq rA       11996)
   Moid-l&i d doM,N -t*           e!nb$ by tHrlB rsdRN t{lYmd or
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  tat.Bo,   J6st     101x,   ,p17-55

            NEUROCFEMICAI, AND EXIRAP}TATIIDAL ETFECTS
             OF ATYPICAI NEIJROLEPITC CLOZAPINE II\ RA.I.S

                         FARU^r BATOO!, Z
                                       S, SArr.y,' M. A, H^L!EMi
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                                AND
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     .                      II4{TERLTI,S AND METBOIIS
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 Prlv6'      1994,816141l,,2001)




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                                .{C(NOWLEDCEMENTS
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