LSD Psychotropic drugs Ed by Garattini Ghetti Elsevier by mikesanye


									                      LSD            539

                      Psychotropic                             drugs.                    S.Garattini_
                     Elsevier,                          Amsterdam_     London,                                    New              York_
                     Princeton                          1957,   p.313.

             PHARMACOLOGICAL                                   ACTIONS                FROM INTRACEREBRAL

                                                         DRUG INJECTIONS

                                                             THOMAS          J. HALEY

                           Division o[ Pharmacology   and Toxicology, Atomic Energy Proiect,
                          School o[ Medicine, University o[ Cali[ornia, Los Angeles (U.S.A.)"

Recently,          there     has been a revival                of interest           in the effects           produced             by the        direct
introduction              of drugs        into     the     brain       ventricles.          The   technique                 is not      new,     but      the
development of the implanted cannula for cats (FELDBERG AND SHERWOOD *) and                                                                             dogs
(HALEr AND DICKlXSOY 8) has made possible    repeated injections of drugs in the                                                                       same
animal   with   a minimum      of difficulty.   Thus far, more than    forty  drugs  have   been
studied   by this technique.     From    this large number  of agents,   we have selected    one
psychotomimetic      agent, lysergic   acid diethylamide,  and one psychotherapeutic      agent,
reserpine,          for    discussion.           This     discussion        will consider              the     effects        produced           and      the
possible       central        sites involved     in these effects. Moreover,                             it will be pointed                   out that,
although         drugs        have    the ability     to cause a profound                               discharge   of the                   autonomic
nervous    system,             each      drug      appears         to have       more       specific         effects        on selected          areas        in
the brain.


Under         pentobarbital               anesthesia,           cannulae             were     implanted                in    the     third        cerebral
ventricle          of five dogs          according           to HALEY            AND DICKINSON s and                         in the      right      lateral
ventricle          of nine     cats    according           to FELDBERt;              A._D SHERWOODL                     Injections           of drugs         in
isotonic   sodium    chloride solution were made once a week. The total volume                                                                    injected
 was o.5-1.o    ml in dogs and o.25 ml in cats. The various doses of lysergic acid                                                                 diethyl-
amide        and     reserpine        used       are given         in the    text.


L ysergic       acid diethylamide                 (LSD-25)

In the       dog,     an intraventricular                  injection        of 20 _g of LSD                  caused          scratching,           shaking
of the head and whining. J'hirtv                            minutes later, the animal                        was calm and                quiet.        When
the dos,. of LSD was increased                              to 50 /*g, licking of the                        lips, shaking               of the        head,
salivation,          retching,        emesis,           micturition         and       tachypnea          occurred              within        4 minutes.
The pupillary              reaction     to light          was not modified  and ability to follow commands     was
not impaired.              Hytx'r_nsitivity               to sound and touch did not occur. The animals    became
frightt'ned          and     their    behavior          resembled         that       of a puppy          placed             in strange         surround-

     • This article is based in part on work performed    under Contract AT-o4-I-GEN-12 between
the United States Atomic Energy Commission and the University of California at Los Angeles,
and in part on a grant from Ciba l'harmaceutical    Products, Inc.
He¢erenccs p. 3t,_'.
314                                           T.J.H.\LEY

ings. Salivation  was still present 90 minutes after injection.            The animals aptmared
to return to their pre-iniection   behavior after 2IO minutes.            Increasing the dose to
ioo-I4O   p.g resulted in the same effects seen at the lower doses and, in addition,
mydriasis    with reactive  pupils, tachypnea     followed by bradypnea, ataxia  and an
apparent    increase in the frightened   behavior. Salivation continued long after the
other effects were absent. The animals appeared normal 24 hours later. In all experi-
ments, regardless of the dose of LSD, prolonged      periods of howling occurred           when the
animals were returned     to their cages.
     In the cat, an intraventricular    injection of 34-37.5 P-g of LSD caused             mydria_sis
with reactive pupils within I minute. There was a hypersensitivity  to light and sound
and in some instances to touch. Sensitivity to sound had a duration of 15 minutes. The
animals tended to remain in one place, and if induced to walk, would slink from one
place to another.       Sweating   occurred   in four cats as evidenced   by moist foot pads and
imprints   left on the cage floor. Throughout     the entire period of acute response,      30
minutes, the animals appeared     frightened and wished to be left alone, but they could
be petted. When the dose of LSD was increased         to 75-I2O _g, similar responses were
obtained.   The animals were hypersensitive     to light and avoided direct light in their
eyes. There was only a slight response to sound. Tile fear response was accentuated,
but the animals would attack        only if continuously     irritated. Micturition  without
 ceremonial occurred. Recovery from the acute effects of LSD occurred within I hour.
 Increasing the dose to I25-21o p.g, accentuated      the fear of the animals and resulted
 in crouching in the corner of the cage farthest from the observer.      Immediately    after
injection, the following changes were observed: licking of the lips, salivation,  sweating,
mydriasis   with reactive pupils, slight sen_itivitv to sound, slight sensitivity   to light
and avoidance of direct light in the eyes. The animals did not wish to be petted but
would only attack if provoked.    This response was not the same as the "sham rage"
observed by GADI)V._t ._._I) VO6T 4 after 8oo /_g of LSD. Depression     but no catatonia
was observed.  In this regard the results differed from those reported by STURTEWtNT
A._O DRILLtL However, such responses      must be compared to the pre-injection       state
of the animal. Both depression and fear are much accentuated     in those animals which
are either depressed or fearful prior to LSD iniection.
     Upon the basis of the above behavioral changes                 and evidence   of autonomic
 nervous system discharge,       it is logical to question   the role of the brain in various
 phenomena     observed. This is of particular    importance    because HALEr A._D RVTSCH-
 MA._,_ found only 8-1o% of the dose of LSI) in the brain of cats IO minutes              after
 injection, although drug effects were very evident. This indicates a high efficiency of
 the blood-brain    barrier in removing LSD from contact with vital brain areas and the
 extremely    low concentrations  of drug       required   to cause profound   temporary     changes
 in central   nervous system activity.


 In dogs, the intraventricular injection of 25 -5o _g of reserpine produced immediately,
 salivation, retching and repeated     emesis. When the dose was increased        to 31o wg,
 salivation, repeated emesis with regurgitation    of lille, defl_cation and a slight miosis
 were observed, l';lectrocardiographic      changes consisted of tachycardia,  a bipha.sic or
 inverted T-waw., and an accentuated         P-wave. No residual effects were seen 24 hours
  later and the animals appeared     normal.
 I¢.,'/cren_ p .it,_;
                               EFFECTS      OF   INTRA('FREI_RAI.         DRUG    INJE(:TIONS                         315

        In cats,     io-16     tLg of reserpine      intraventricularly          were ineffective.     This confirmed
the observation   of GADDU._I AND VO(;Ta. After a latent period of 30 minutes, 18--2o _.g
of drug caused relaxation     of the nictitating    membrane,  miosis, narrowing of the palt)e-
 bral fissure to a slit, squinting in response to light, withdrawal      to ttle darkest corner
of the cage, diarrhea,      anorexia,   tranquilization    and a pronounced     generalized  de-
 pression. Normally aggressive cats became docile, and fearful cats became friendly.
When the dose of reserpine was increased to 4° p.g, the same responses were obtained,
but the latent period before onset was reduced to 2o minutes. These results agree with
the known actions of reserpine and disagree with those of STURTEVANT ANI) DRILL 16
who observed an autonomic nervous system      discharge followed by typical reserpine
effects 24 hours later. The differences are probably   related to the Ioo p.g dose of
reserpine  used by STURTEVANT AND DRILL 16.
     Because available evidence indicates that very little reserpine is localized in the
brain (NuMEROFF el al._°; SHEPPARD el aI.14; GLAZKO el al. _) and the drug is hydrolyzed
and converted   into tfimethoxybenzoic    acid, reserpic acid and methylreserpate,
these substances were also injected intracerebrally.    5-Hydroxytryptamine      was in-
cluded because reserpine releases this substance in the brain. Intracerebral      injection
of 20 /zg of trimethoxybenzoic     acid produced no reaction.  Increasing   tile dose to 4 °
/,g resulted in decreased alertness and a slight anorexia, although     the animals would
eat if encouraged to do so. Thus, it appears that the effects observed after reserpine
are not related to trimetboxybenzoic       acid, although the doses of this latter compound
were approximately       three times greater than the former based upon molecular weight.
 Intracerebral   administration    of 20/zg of reserpic acid produced only defecation,        and
the animals appeared normal and consumed their usual quantity of food. Increasing
the dose of reserpic acid to 4°/,g caused a decreased alertness,      but no tranquilization.
One cat developed convulsive seizures affecting the left side, 57 minutes after injection.
These seizures were of 30 seconds duration in the beginning but became continuous
after I }_ hours. They could be induced by loud noises. During the seizures, the cat
had a vacant stare, mydriasis, piloerection,      and continuously   howled. Intraperitoneal
injection    of 30 mg/kg of sodium pentobarbital        anesthetized the cat and terminated
tile convulsions.   Intracerebral  injection  of 20-40 t*g of methylreserpate   produced  no
effect in the cats, other than a slight decrease in alertness. These data indicate that the
central effects of reserpine             are related to the compound              itself and not to its metabolic


From        tile data     presented,     it is evident     that     LSD and reserpine           have   certain   similar
actions which may be related to autonomic                            nervous system discharge.  Many other
drugs also have such properties and these                           have been summarized    in Table I. The
possible      sites of action      listed   are derived       from electrophysiological            studies   of others
and should not be considered as the only sites of action because activation                              of receptors
in the cerebral ventricles  may, through interneuronal    pathways,   cause                              more distant
centers to be affected (H._H.:v6,7). Furthermore, it would he inconsistent                               to insist that
certain      specific     sites in the walls of the ventricles               are the only ones         ln, ing affected,
Ix'cause the brain            ventricles  form a closed system and the drugs                       would eventually
spread throughout              the entire system. Tile possibility of diffusion                    into the mass of
Relcremcs      p. 31,_.
316                                                       T.J.    HALEY

                                                               TABLE    I


pharmacologicaleOect                            EOective drugs                            Possiblecentral sites ol action

Salivation                   LSD, Mescaline, 5-HT, Reserpine,                 Pre-optic hypothalamus.             Salivatory
                             Strophanthin     derivatives, Procain-           nuclei of medulla
                             amide, Curare, Histamine,     Hexa-
                             methonium,     Decamethonium,      Ban-
                             thine, Atropine,    Molphine,  Ergo-

Retching                     LSD, Mescaline, Reserpine,      Stro-            Brain stem reticular         formation
                             phanthin    derivatives,  5-HT, Quinidine,
                             Acetylcholine,     ATP, Adrenaline,
                             Histamine,     Hexamethonium

Emesis                       LSD, Reserpine,    Strophanthin     de-          Chemoreceptor      trigger zone of IV
                             rivatives, Adrenaline,   Hexametho-              ventricle.  Caudal portion of di-
                             nium, Decamethonium,        Banthine,            encephalon.    Ependymal     receptors in
                             Atropine,  Curare, Frenquel,     Bulbo-          lateral ventricle

Mydriasis                    LSD, Reserpine,      Mescaline, Stro-            Posterior hypothalamus.   Centers              in
                             phanthin   derivatives,  Chlorpromazine,         cerebral cortex and brain stem
                             Quinidine,   Ergonovine

i'qystagmus                  Strophanthin       derivatives,     Quinidine,   Pontine area or medial          longitudinal
                             Procainamide,       Banthine                     fasciculus

Defecation                   LSD, Chlorpromazine,        Reserpine,           Hypothalamic          pre-optic and supra-
                             Strophanthin   derivatives,     Procain-         optic nuclear      areas. Medulla oblongata
                             amide, Quinidine,    Adrenaline,     ATP,
                             Histamine,   Hexamethonium,         Deca-
                             methonium,    Banthine, Curare,

Micturition                  LSD, Mescaline, Strophanthin                     Pre-optic  hypothalamus.    Autonomic
                             derivatives. Quinidine                           centers in diencephalon. Centers in
                                                                              rostral border of hind brain

Vasoconstriction             Strophanthin       derivatives,     Quinidine    l'osterior hypothalamusVasomotor
                                                                              center in medulla

Shivering                    ('hlorpromazine,       Strophanthin              Posterior      laypothalamus

Tachypnea                    LSD, 5-HT, Strophanthin        deriva-           Respiratory       center   in medulla
                             tires, ATI', ttistamine,   Hcxa-
                             methonium,     I)ecamethonium,
                             Banthine,   Atropine, Curare, Frenquel

l_radypnea                   ('hlorpromazine,       Reserpine                 l(espiratory      center   in medulla

I.achrimation                Mescaline,     ltistamine                        Mammillary     body to nucleus of VII 1
                                                                              nerve. Area _ ,,f cerebral cortex
                                                                               through stimulation   of anterior hypo-

Re/cremes       p   31,_.
                                     EFFFCTS           OF     INTRACEREBRAL                     I)RUG       INJECTIONS                                                3Z7

                                                                          TABLE         II

                                 SPECIAL       EFFECTS            AFTER       INTRACEREBRAL              DRUG      INJECTION

 PkaT_acoiogical         e_ect                            Effective drugs                                                Possible cereal sites o] action

Abnormal                         Chlorpromazine.                  Strophanthin                       Anterior       and posterior               hypothalamus
electrocardiogram                derivatives

State   III. Plane lI.            Procainamide,            Quinidine.                               Ascending             reticular         system;        hypo-
General     anesthesia            Adrenaline,           Nor-adrenaline                              thalamus

Analgesia                        Chlorpromazine                                                     Hypothalamus                  and       brain       stem

Tranquilization                  Chlorpromazine,                  Reserpine,      Frenquel          Hypothalamus                  and       brain       stem

Hypothermia                      Chlorpromazine                                                     Thermoregulator                    center

Miosis                           Reserpine                                                          Optic        chiasma,             optic      tract,        pretectal

Ataxia                           LSD,      Mescaline,             Chlorproniazine,                  Motor         area       IV       of    cortex.        Vermis          of
                                 ATP, Hexamethonium,                       Frenquel,                cerebellum

llchavior          changes       LSD.      Mescaline.             Ergonovine                         ?

('atatonia         and           LSD, Acetylcholine,       Eserine,     I)FP,                       Region  of periventricular                         gray matter.
 depression                      Bulbocapnine,     Mescaline.      ( hlor-                          Area immediately         above                    mammillary
                                 promazine,    Reserpine..Morphine                                  bodies and rostral      to red                    nuclei

Sweating                         I,SI)                                                              Centers        in hypothalamus.                       Pre-motor
                                                                                                    cortex.       IV ventricle  and                 a center    in the

Sham        rage                 I.SI),    Murphiiae,             Bulbocapnine                      l'osterior       hypothalamus                     bordering
                                                                                                    tegmentum           I11 ventricle                 lining    caudad
                                                                                                    to   entry      of aqueduct

•Scratching                      Mescaline,          5-tiT,       Morphine,      Eserine,           Distal        wall      of    IV       ventricle.          Anterior
                                 I)I"1'                                                             intraventricular                  portion         of forntx
                                                                                                     nuclei       of septum                pcllucidum            to an-
                                                                                                    terior       commissure                above      and        behind
                                                                                                    Inammillary              bodies

t ,rex ul_i,m_                   5-tiT,     1 )I"P,     .\cetyh       hohut.,    t ularv.           4 entrencephallc               system           of higher       brain
                                 la]tll[_)capnirlt       ,, Eserlne,       Rt,serplt        ,itld   stein

l¢,t¢_,_z,,s        p    3is
318                                                            t, J. HALEr

brain tissue surrounding       the ventricles     must also be considered.  The effect of the
blood-brain    barrier in reducing the available amount of drug may explain in part the
duration    of action of any given drug, but tissue or receptor attachment        and metab-
olism are also involved.-The      interrelationships   between chemical structure  and site of
action are difficult to interpret, because so many diverse drugs appear to affect tilt,
same areas. However, certain drugs appear to have very" specific effects on certain
areas (set' "lal)lc II), The diversity of action between LSD and reserpine and the
correlation   between observed    symptoms    and known effects ill the central nervous
system      can readily   be seen. Pt'RPUR.O = reported that                                          lot" doses of LSD produced
facilitation    of the-evoked   auditory and visual primary                                           responses while higher doses
depressed the auditory responses but continued to facilitate the visual ones. Tiffs
coincides with our observations of the changes occurring in the sensitivity of tile cat
to sound and light. The tranquilization   oI the cat by intracerebral reserpine agrees
with tile suggestion   of SCHNEIDER AND EARl- la that changes have been produced       in
the central regulating   mechanism of the autonomic   nervous system in the brain stem.
The other changes observed support the suggestion                                                  of BEIN et al) that inhibition     of
the sympathetic     areas of the posterior hypothalamus                                             has occurred.  However,    further
investigation   is necessary to localize more precisely                                           the exact sites of activity of both
LSD and reserpine               in the central           nervous             system.


 lntracerebral injection of LSD in conscious dogs and cats results in a profound activation of the
 autonomic nervons system producing salivation, retching, emesis, micturition and reactive pupils.
 Sweating and a hypersensitivity to light, sound, and touch, was observed in the cats. At the doses
  used, "sham rage" (lid not occur, but the animals would attack if continuously irritated. Ataxia
  was observed in the dogs. In both dogs and cats, a fear complex was induced by LSD. Intracerebral
  injection of reserpine in conscious dogs produced an autonomic nervous system discharge similar
  to that observed after I.SD. In cats, reserpine produced relaxation of the nictitating membrane,
  miosis, narrowing of the palpebral fissure to a slit, avoidance of light, diarrhea, anorexia and
  tranquilization.   Equivalent doses of trimethoxybenzoic     acid, reserpic acid or methylreserpate
  did not produce such effects indicating that these reserpine metabolites are not involved in reser-
  pine action. The possible central sites _f action of I.SD and reserpine have been outlined and their
  actions compared with those of other drugs.


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