Dietary Tyrosine Protects Striatal Dopamine Receptors from the

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Dietary Tyrosine Protects Striatal Dopamine Receptors
from the Adverse Effects of REM Sleep Deprivation*
ANWAR HAMDI a, JEFFERY W. BROCK b.t, SHORYE PAYNE b, KEITH D. ROSSb,
STEVEN P. B O N D h n d CHANDAN PRASADC

aDevnrtment oj Pkarmacology, King Saud University College of Medicine, Abha, Saudi Arabia;
\~eurobrilaviorai Research Institute. Nashville, Tennessee 37211, U S A :'Section of Endocrinology, Department of hledicine,
Louisiaila State Unioersity Medical Center, Neur Orleans, Louisiana 70112, U S A


(Rece~nedI0 September 1997)

 L-Tyrosine is a non-essential amino acid that is                     catalepsy compared to the corresponding CC group,
 produced as an intermediaq metabolite in the                         while the RSD group consuming tyrosine showed a
 conversion of phenylalanine to3,4-dihyroxyphenyl-                    catalepsy that was significantly increased, and
 alanine (DOPA), and is a precursor of the neuro-                     similar to that of cage control animals o n a control
 transmitter dopamine. In previous studies, tyrosine                  diet. These data suggest that the tyrosine-supple-
 pretreatment was shown to protect against the                        mented diet significantly attenuated RSD-induced
 neurochemical and behavioral deficits of acute stress                changes i n striatal dopamine D2receptors, and the
 caused by tail shock or cold exposure in rodents. The                effect appeared sufficient to influence RSD-induced
 present study addressed the hypothesis that tyrosine                 behaviors.
 administration may be an effective counter-measure
 to dopamine-mediated behaviors induced by rapid
 eye-movement sleep deprivation (RSD). In order                       K q c ~ o r d s :REM sleep deprivation, Dopamine receptors,
 to test the hypothesis, Sprague-Dawiey rats were                     Tyrosine
 divided into 9 treatment groups: RSD-treated rats on
 normal-protein diet (20% casein: 1% tyrosine, 1%
valine); tank control (TC) on a normal diet; cage
                             rats                                     INTRODUCTION
control (CC) rats on normal diet; RSD-treated rats on
4 5 tyrosine diet; T C rats on 4% tyrosine diet; CC rats
on 4% tyrosine diet; RSD-treated rats on 4 6 valine                  One of the most common sources of stress in
diet; TC rats on 4% valine diet; CC rats on 4% vaiine                humans, and one which has the most profound
diet. In the RSD group receiving tyrosine, there was
no apparent change in B,,         for binding of the                 detrimental effects on brain function, is loss of
dopamine D2receptor ligand l3H1Ykf-09151-2 the    in                 sleep (Speigel, 1981). Subjective attitude appears
striata as compared to the respective TC and CC                      to be severely affected by sleep reduction, i.e.,
groups; whereas RSD-treated rats maintained o n the                  appearance, mood, and behavior (Handbook of
normal diet and valine supplementation demon-
strated expected increases in B,,   for ligand binding.              Humall Eltgineerin~Dnfa, 1952). Total or partial
The TC group on the tyrosine diet showed attenuated                  sleep loss results in chronic excessive fatigue,

 'This work was performed at [he Penn~ng~on   B~omedicalResearch Center. 6400 Perkins Road. Baton Rouse. LA 708OS.
 'Corresponding author. Address tor Correspondence: Division of Adult and Child Health, Kentucky Department ior Public
Health. 275 East Main Street. Frankfort,Kentucky 40611, USA.E-mail address: jbrocklBmail.state.ky.us.
 110                                               A. HXiMDI et al.


  lowered motivation to work, and poor job                  effectiveness as an antidepressant (Mouret et al.,
  performance leading to frustrations and conflict          1988), although not all studies are in agTeement
  with others. Apprehension, and not sleep loss             (Gelenberg et a!., 1990; Wolfe et nl., 1989).
  alone, has often been cited as a cause of                 Investigators for the U.S. Army have demon-
  performance decrement in sleep deprivation                strated a considerable body of evidence that
  studies (Naitoh et a/., 1990). For workers needing        tyrosine administration may be an effective
  maximum alertness and unintempted concen-                 countermeasure to anxiety, mood deterioration,
  tration, anxiety or stress associated with sleep          and the stress-related performance decrements
  deprivation may increase the likelihood of                in soldiers (Bandaret and Lieberman, 1989;
  performance errors. Activation of the central             Owasoyo et al., 1992; Rauch and Lieberman,
  dopaminergc system may be important in the               1990; Salter, 1989). Oral tyrosine was able to
  etiology of sleepde p rivation-induced behavioral         protect humans from some of the adverse
  changes (Carlini, 1983). Evidence from many               consequences of cold exposure and hypoxia
  studies suggest that changes in central dopamine          (Bandaret and Lieberman, 1989; Shukitt-Hale
  receptors are associated with deprivation of             et al., 1996). The effectiveness of tyrosine in
  rapid eye-movement (REM) sleep (Carlini, 1983;           counteracting the effects of hypothermia were
  Demontis et al., 1990; Ferguson and Dement,              reproducible in rats (Ahlers, 1992; Rauch and
 1969; Fratta et a!., 1987; Trampus and Ongini,            Lieberman, 1990). In humans, tyrosine was
 1990; Trampus et al., 1991; Tufik et al., 1978; 1987).    shown to be effective in attenuating the physio-
 Our group has reported that rapid eye-move-               logical effects of lower body negative pressure
  ment sleep deprivation ( E D ) in rats was               (reduced systolic blood pressure, increased heart
 associated with a sigruficant increase in the             rate, depression, tension, and anxiety) (Dollins
 density of both dopamine Dl and D2 receptor               et al., 1995)and performance in perceptual motor
 subtypes in the striatum (Hamdi et al., 1993) and         tasks (Deijen and Orlebeke, 1994).
 frontal cortex (Brock et al., 1995),compared to the          The present study was performed to test the
 tank-control group. These data are consistent             hypothesis that dietary tyrosine supplemen-
 with the theory that the E D results in an                tation attenuates RSD-induced facilitation of
 increase in central dopaminergic activity.               dopamine-mediated behaviors in the rat, i.e.,
    There is experimental evidence to suggest that         RSD-induced increase in spontaneous locomotor
 appropriate dietary manipulation may alter               activity, decrease in drug-induced yawning, and
 brain function in a manner that prevents or              decrease in drug-induced catelepsy. The study
 compensates for the effects of RSD. One dietary          also examined the effect of tyrosine supplemen-
 entity that may be useful is tyrosine, a non-            tation on striatal dopamine receptor binding
 essential amino acid which is produced as an             characteristics after sleep deprivation (Hamdi
 intermediary metabolite in the conversion of             et al., 1993). The behavioral measurements in-
 phenylalanine to 3,3-dihydroxyphenylalanine              cluded spontaneous locomotor activity, dmg-
 (DOPA), and is a precursor in the synthesis of           induced yawning, and drug-induced catalepsy.
 dopamine and norepinephrine (Bender, 1985).              Locomotor activity was an appropriate behavior
Animal studies have shown that a diet consisting          to measure in this study because: (1) hyperactiv-
of 4% tyrosine by dry weight may increase brain           ity is one of the salient features of sleep
concentrations of catecholamine, thus improving           deprivation in rodents (Albert et a/., 1970;
neurotransmission and compensating for stress-            Asakura et al., 1993; Carlini, 1983; Oniani, 19841,
induced catecholamine depletion in the brain              thus it provides an indirect validation that our
(Lehnert et al., 1984). In humans, tyrosine admin-        methodology was sufficient to produce the
istration has been shown to have some clinical            desired effect in the rats, and (2) there is a strong
                       REM SLEEP DEPRIVATION AND DIETARY TYROSINE SUPPLEMENTATION


 correlation between locomotor behavior and
                '                                        et al., 1984).Valine, a branched-chain amino acid
 central dopaminergic activity (Costall et al., 1977;    that competes with tyrosine for uptake into the
 Fink and Smith, 1980; Ranje and Ungerstedt,             brain but does not act as a precursor for
  1977). Yawning is believed to be a behavioral          dopamine, was included in this study in order
 consequence of decreased central dopaminergic           to control for potential nonspecific effects of
 neurotransmission (Mogilnicka and Klimek,               tyrosine supplementation. The precise constitu-
 1977; Serra et al., 1986; 1987).Catalepsy is a form     ents of the diets are presented in Table I. After the
 of immobility in which the animal remains in an         rats were adapted to the diets for 7 days, they
 imposed abnormal posture (Coyle et al., 1983).          were introduced to the sleep deprivation proto-
 This is typically induced in rats by the adminis-       col or one of the two control protocols described
 tration of dopamine receptor antagonists (Costall       below. For all animals in this study, body weights
 and Olley, 1971).                                       and daily caloric intake were recorded immedi-
                                                         ately prior to entering into a treatment protocol
                                                         (baseline) and every 24h for the duration of
 METHODS
                                                         treatment.
 Subjects
                                                         Sleep Deprivation Treatment
Male Sprague-Dawley rats (290-300 g; Harlan
Sprague Daurley, Indianapolis, I )N were housed           The animals on each of the three diets were
individually at controlled temperature (22-23°C)          further divided into three subgroups: ('1) rats that
and 12-h light-dark cycle (light on at 7a.m., both        were deprived of rapid eye-movement sleep
before and during the sleep deprivation proto-            (RSD group) by residing in the watertank on
col) with food and water ad Gbitum. The animals           small pedestals (6.5 cm diameter) for 96 h, (2) the
were divided into 3 groups initially (N= and
                                          18),            tank-control rats (TC group), which resided in
maintained on one of the following diets: the             the watertank on large pedestals (13cm diam-
more commonly used normal-protein diet (NP;               eter) for 96h, and (3) the cage-control rats
1% tyrosine, 1% valine; Ilumas et al., 19721, 4%          (CC group), which resided in their home cages
tyrosine diet (Tyr), or 4% valine (Val) (Lehnert         for the duration of the 96-h procedure, receiving
                                                         only controlled handling (3 min/day). The ped-
        TABLE I Composition of the purified diets        estals were surrounded by water (20°C), kept at a
Constituent                 Diets (g/kg dry wt.)
                                                         level to within 1 crn of the edge of the pedestals,
                                                         and the tanks were cleaned daily. Rats that
                      Normal     Tyrosine-     Valine-
                                                         resided on the small pedestals were able to
                                 enriched     enriched
                                                         experience all stages of sleep except the rapid
Casein                                                   eye-movement (REM) stage, at which point they
L-tyrosine
L-valine                                                 were awakened when they lost muscle tone and
Sucrose                                                  fell toward the water. In order to control for the
Corn starch                                              stress response that results from isolation, motor
Corn oil
Cellulose
                                                         restriction, novel environment, and falling into
DL-methionine                                            water, a watertank-stress control group (tank
Salt Mixture                                             control or TC group) was included in the study.
Vitamin Mixture
                                                         All rats continued to have free access to the
Choline bitartrate
                                                         respective diet and drinking water during the
Total (gm)                                               treatments. The validity of the platform technique
kcai / kg
                                                         for RSD in rats has been reviewed elsewhere
(Brock et al., 1995; Hicks et al., 1977; Vogel, 1975).   dissolving in a minimum quantity of 90%
In brief, it is.recognized that there can be large       ethanol and dilution with distilled water.
variations in the absolute amount of REM sleep           Catalepsy This behavior was measured in the
deprivation the animals may experience from              rats beginning 30mln post-adm~nistration of
one study to another (Hartman and Stern, 1972;                                      l
                                                         the selective dopamine D receptor antagonist
Mendelson et al., 1974) and that the tank-control        SCH23390 (50 pg/kg i.p.) (Meller et nl., 1985).
group is not universally accepted as adequately          Measurements were made 3 times over a period
controlling for all imaginable types of stress           of one hour (i.e., every 20min). The test was
which may be associated with residing on the             performed by placing the forepaws of the rat
small pedestal. Nonetheless, the platform tech-          over a horizontal steel rod (0.9cm diameter)
nique remains the most frequently used method            pos~tionedlOcm above the surface of the test-
for selectively depriving rodents of REM sleep           ing area, and recording with stopwatch the time
(Asakura et al., 1992; 1993; Bondarenko et al.,          taken for the rat to remove both paws from the
1990), without the need for EEG monitoring               bar (120-s cut-off) (Kinon and Kane, 1989;
(Vogel, 1975).                                           Lappalainen et al., 1989). SCH23390 hydrochlor-
                                                         ide (Research Biochemicals Inc., Natick, MA)
                                                         was prepared for injection by dissolving in a
Behavioral Testing                                       minimum quantity of 90% ethanol and dilution
At the beginning of the sleep deprivation treat-         with distilled water.
ment, the animals of CC group were transferred
in their home cages to the treatment room along
with the animals of groups RSD and TC. All               Radioligand Binding
behavioral observations were_ made between
                                                         At the end of the treatments, rats were sacrificed
noon and 2:00 p.m., following 96 h of REM sleep
                                                         by decapitation during the light cycle, between
deprivation.
                                                         noon and 2:OOp.m.. The striata were dissected
 Spontaneous Locomotor Activity After being              and stored at - 8 0 0 ~until the binding assays
 treated in the sleep deprivation paradigm for            were performed. Binding of [ 3 ~ ] - ~ - 0 9 1 5 1to2
                                                                                                             -
96 the rats were placed in individual activity
  hl                                                     the D2dopamine receptors (Terai et al., 1989) was
cages (46x'3x23 cm) equipped with the Opt@               carried out using the striatal membranes, as
Varirnex mini Vstem                  Instruments?        previously described (Hamdi et al., 1993). Tissues
OH) for activity measurements. The animal cage           from individual rats were homogenized (ver:
was placed between optical sensors (emitters             tishear Polytron, setting at 60 for 20s) in 5 ml of
and detectors) which monitored and recorded              ice-coid buffer A (50 m~ -rris-~cl,8 m~ M ~ c            ~   ~
the rat's ambulatory activity. Spontaneous loco-         5 m l EDTA, p~ 7.15). ~h~ homogenate was
                                                                 ~
motor activity was recorded for 15min.                   centrifuged (48,000g for 20min at 4 ' 0 . The
Yazcning This behavior was observed in the               homogenization and centrifugation were re-
rats as they resided in their respective water-          peated twice. The final pellet was resuspended
tanks (RSD and TC groups) and in their home              in buffer B (50mlM Tris-HC1 containing 0.1%
cages (CC group). Yawning was quantitated in             ascorbic acid, 10 pM pargyline hydrochloride,
each rat for 30 min following administration of          and ions as follows: 120 mM NaCi, 5 mM KC1,
the dopamine D2 receptor agonist quinpirole              5 mM MgC12, 1.5 mM CaC13, 1 mM EDTA, pH 7.4
(50pg/kg i.p.) (Serra et a/., 1987). (-)-Quinpir-        at 25°C) and used for the binding assay. The
ole hydrochloride (Research Biochemicals Inc.,           incubation mixture (1.5 ml) for receptor assay con-
Natick, MA) was prepared for injection by                tained: 150 pg membrane protein and 10-200 pM
                        REM SLEEP DEPRIVATION AND DIETARY TYROSINE SUPPLEMENTATION                                     123

(seven different concentrations of radioligand).                 influence of multiple procedures on interpreta-
The tubes were incubated at 25OC for 90min in                    tion of the data. All data were analyzed by
the dark. The membrane-bound radioactivity                       analysis of variance (ANOVA) followed by
was separated from the free, unbound radio-                      Newman Keuls test. Statistical significance was
activity by rapid filtration under vacuum                        accepted at the 95% confidence level. The
through Whatman GF/B filters with four 4-ml                      siatistical data presented herein show the with-
rinses with ice-cold buffer B (pH 7.4 at 25'0. The               in-diet effects of sleep deprivation treatment and
membrane-associated radioactivity was mea-                       its relevant controls: (1) RSD group versus TC
sured in 10 ml of ScintiverseII scintillation fluid              group, and (2) TC group versus CC group.
in a Beckman liquid scintillation counter at an
efficiency of 55-60%. Non-specific binding for
the D2 receptor binding assay was defined in the                 RESULTS
presence of 30 p M (-1 sulpiride, and represented
about 15-36% of the total binding. The specific                  Prior to introduction of the respective treatment
binding data from each treatment group were                      protocols, there were no differences among the
analyzed separately using a nonlinear regression                 groups with regard to body weights and daily
analysis (the computer program Graphpad, IS1                     caloric intake (Table IIA and IIB). During the
Software, Philadelphia, PA) to g v e the estimates               course of treatment, there was a tendency for
of the maximal density (B,,,)     and the affinity               body weights to decline in all TC and RSD
(&I values. Protein determinations were per-                     groups, but the differences were not statistically
formed using a bicinchoninic acid (BCA) protein                  s i g h c a n t . However, daily caloric intake in-
assay k t (Pierce Chemical Co.1.                                 creased in all groups receiving 96 h of RSD,
                                                                 regardless of diet (Table W).
                                                                 Spontaneous Locomotor Activity The effects of
Statis tical Analysis
                                                                 sleep deprivation on spontaneous locomotor
The effects of sleep deprivation and diet on                     activity 2 rats maintained on the different diets
different dopamine-mediated behaviors and                        is presented in Figure 1. Among the groups
dopamine receptor binding characteristics were                   maintained on a normal diet, there were no
assessed in a series of studies performed sepa-                  significant differences in ambulatory count
rately. This was done to prevent the confounding                 (F= 0.23; critical F = 4.42). Among the groups


  TABLE I1 Effect of dietary tyrosine supplementation fly),  vaiine supplementation (Val), and normal-protein diet (NP)
  on the body weight [ A Jand daily caloric intake [Bl of rats exposed to 96 h of REM sleep deprivabon (RSD group),
                    T
  watertank-stress C C group), and cage controls (CC group). Values represent MeaniSEM, at baseline/after 96h
  treatment: indicates p < 0.05, treatment vs. baseline
  Group                                    Nonnal diet               4% Valine diet           470 Tyrosine diet

  A. Body Welghts (g)
  CC                                    351 i7.1 /355 L 7.0        352 r 7.0/351 ri: 7.0     358 i7.7/359 5 7.6
  TC                                    364 i7.5/349 2 7.1         357=9.1/347= 10           357 = 8.4/344 2 7.0
  RSD                                   358 c 6.7/341 i3.1         3 8 = 9.5/327 =9.5        355 = 8 . 0 / 3 3 = 8.9

  B. Daily Caloric Intake (g/kg b o d y weight)
  CC                                   53.4 c 3.5/54.0 1 2 . 9    47.6 C 1.5/48.9 5 1.5     51.5 i 2.5/46.3 L 1.8
  TC                                   55.2 i 2.0/62.2 L 2.1      46.65 1.4/61.5 L4.9       53.9 3.0/57.8 C 3.8
  RSD                                  55.7 i3.8/72.4 c 3.0'      47.4 i3.4/75.6 2 4.3'     52.4 i2.0/76.1 i 7.6'
                                                     A. W M D I et al.




                                                                         *   pt0.05   compared




                                          Ambulatory Counts 1 15 minutes
FIGURE 1 Effect of dietary tyrosine supplementation, valine supplementation. and normal-protein diet on spontaneous
locomotor activity in rats exposed to 96 h of RZM sleep deprivation (RSD group), watertank-stress CTC group), and cage
controls (CC group). Values represent ambulatory counts recorded for 15min; MeaniSEM; * indicates p < 0.05, TC group
vs. CC group w i t h d i e t comparisons, o_r RSD group vs. TC group with- diet comparisons.


maintained on valine supplementation, ambula-                was a signhcant watertank-treatment effect (TC
tory counts were significantly increased by both             group vs CC group: F = 6.01; critical F =3.47).
watertank stress and REM sleep deprivation                   Regardless of diet, the TC group showed a
(F= 10.29; critical F = 4.422). Among the groups             signhcant increase in yawning behavior
maintained on tyrosine supplementation, water-               ( p <0.05), compared to the CC group. Sleep
tank stress had no effect on ambulatory counts,              deprivation also had an effect on yawning (RSD
whereas the counts were signhcantly increased                group vs TC group: F = 5.31; critical F = 3.47). As
by 96h of REM sleep deprivation (F=5.49;                     can be seen, RSD caused a significant decrease in
critical F = 4.42). ANOVA also revealed a' sig-              yawning ( p < 0.05) as compared to the TC group.
nificant dietary effect on ambulatory counts                Catalepsy Cataleptic behavior following injec-
among the animal groups that received only                  tion of the dopamine Dl receptor antagonist
RSD treatment, with the tyrosine supplemented               SCH23390 for the different groups is presented
group showing a significantly greater ambula-               in Figure 3. Although measurements of cata-
torv count ( p < 0.051, compared to either the              lepsy were made for ail animals at baseline (i.e.,
normal diet or valine supplementation.                      immediately prior to treatment) and every
Yawning Figure 2 shows the number of drug-                  20minutes post-injection, only the maximum
induced yawns observed in the animals follow-               response latency observed during that time
ing acute injection of the dopamine Dt receptor             period is presented in the table. Baseline for 2!J
agonist quinpirole. The results of ANOVA test-              animals in the study was 2-8s. The results of
ing showed no effect of diet on the number of               ANOVA testing revealed both diet effects and
yawns expressed by the animals. However, there              treatment effects for this behavior. ANOVA
                       REM SLEEP DEPRIVATION AND DIETARY TYROSIPU'E SUPPLEMWTATION




                                             Number of Yawns 1 30 minutes
RGURE 2 Number of yawns induced w i t h 30 minutes following administration of (-)quinpirole (50pg/kg i.p.). Values
represent Mean* SEM; * indicates p < 0.05. TC group vs. CC group within-diet comparisons, or RSD group vs. TC group
withindiet comparisons.




                  4%   Tyrosine                                              p<0.05     compared
                                                                            to TC group




                                               Catalepsy (seconds)
FIGURE 3 Catalepsy responses induced by administration of SCH2.3390(%&kg  i.p.). Values represent maximum latenq
to respond in seconds (MeaniSEM) during a 60-min observation period; indicates p<0.05, TC group vs. CC group
within-diet comparisons, or RSD group vs. TC group withmdiet comparisons.
                                                         AMDI et al.

  revealed significant differences among the                the RSD group demonstrated significantly great-
 groups maintained on the normal-protein diet               er binding density, compared to the TC group
  (F=8.10; critical F=6.41). The TC group de-               ( p < 0.05). Among the groups maintained on
 monstrated significantly less catalepsy than the           valine supplementation, the TC group showed
 CC group ( p < 0.05) and there was not differ-             sigruficantly greater binding density than the CC
 ence between the RSD group and the TC group.               group ( p < 0.05), while the RSD group showed
 Animals maintained on valine supplementation               lower binding density ( p < 0.05). B,,        was
 presented essentially the same pattern of cata-            unchanged in animals maintained on tyrosine
 lepsy as those on the normal diet (F= 10.8;                supplementation regardless of treatment.
 critical F = 6.55). Among the tyrosine-supple-
 mented groups (F= 8.24; critical F = 6.551, TC
 treatment again resulted in sigruficant attenua-           DISCUSSION
 tion of SCH23390-induced catalepsy ( p c 0.05),
 whereas the RSD group demonstrated more                    Oral supplementation of tyrosine, a dopamine
 catalepsy, compared to the TC group ( p < 0.05).           precursor, has been shown to reduce many
                                                            behavioral effects of cold and high-altitude stress
  Radioligand Binding The specific binding of               in humans (Banderet and Liebennan, 1989;
                          1 2
  [ 3 ~ 1 - ~ ~ - 0 9 1 5to -D2 dopamine receptors was      Shukitt-Hale ef al., 1996) and to protect against
  of high affiruty, saturable, and revealed only a          the neurochemical and behavioral deficits of
  single class of binding sites in all radioligand          acute stress caused by tail shock or cold exposure
  assays in all groups. Binding affinity (Kd)      for      in rodents (Lehnert et al., 1984). Animal studies
  the radioligand to sh-iatal homogenates col-              have shown that a diet consisting of 4% tyrosine
  lected from the different animals groups is               by dry weight may increase brain concentrations
 shown in Figure 4. ANOVA testing revealed a                of norepinephrine, thus improving neurotrans-
  signlhcant treatment effect (F=4.06; critical             mission and compensating for stress-induced
 F = 2.491, wherein the TC group demonstrated               norepinephrine depletion in the brain (Lehnert
 significantly higher ligand binding affinity               et al., 1984). Tyrosine administration appears to
 (lower Kd) as compared to the CC group when                result in at least transient increases in both
 animals were maintained on the norma1 diet                 norepinephme (Gibson and Wurtman, 1978)
 ( p < 0.05). Also, when animals were maintained           and dopamine ~Durxng al., 1989) in the brain.
                                                                                     et
 on the valine diet, ligand binding affiruty for               Early attempts to establish a direct relationship
 the TC group was lower (higher &) than that                between tyrosine availability and catecholamine
 of the CC group ( p < 0.05). & was unchanged              synthesis led to conflicting results (Kaneyuki
in animals maintained on tyrosine supplemen-               et al., 1984; Rasmussen et al., 1983). However, it
 tation regardless of treatment. Also shown in             is now well-established that most of the conflict
                                        B,)
 Figure 4 is the calculated density (,, of [ 3 ~ ] -       was related to the degree of stress to which the
YM-09151-2 binding to striatal homogenates                 study animals were subjected. The theory held by
collected from the different animal groups. The            current investigators is that catecholaminergic
results of ANOVA testing revealed sigruhcant               nerves are not sensitive to the presence of excess
diet effects and treatment effects (F= 13.7; cri-          tyrosine while at rest, but become sensitive when
tical F = 2.49). Among those groups maintained             the nerves are activated by stress (Hjemdahl et al.,
on normal diet, a pattern of changes similar to            1989; Roth et al., 1982; Weiss et al., 1981). This
the changes in Kd was observed. The TC group               theory is consistent with work from both human
demonstrated significantly lower binding den-              (Growden ef al., 1982) and animal studies
sity as compared to CC group ( p < 0.051, while            (Lehnert et al., 1984). Acceptance of the theory is
                       RUI SLEEP DEPRIVATION AND DmARY lYROSLNE SUPPLEMENTATION




                       J-I
                                                          Bindino Atfinif"                (KdJ
                                                                 p4.05 compared to TC group
                                                                                                     1

                                      Normal               4% Valine             4% Tyrosine




                       -
                       E
                       a C
                        I ,
                              a:
                               (
                                  :   cco-p
                                                  Maximum Bindina Densitv / B m x )              :
                        2         .   rcaup
                                      prou up
                                                       *pd.OS compared to       TC group




                              -
                                      Normal              4% Valino            4% Tyrosine

                                                          DIET
FIGURE 4 Results of saturation of [3Hl-~~-09151-2 dopamine Dzreceptors in striatal homogenates collected from ani-
                                                        to
mals maintained under normal-protein diet, valine supplementation, and y o s i n e supplementation, in addition to REM
sleep deprivation (RSD). watertank control (TC) or cage (CC) treatment; [upper panel] binding affinity (Kd in pM) and
[lower panel] receptor binding density (
                                       B
                                       ,    in h o l / m g of protein). Values represent (Mean *SD)for individual saturation
isotherms; indicates p < 0.05, TC group vs. CC group withn-diet comparisons, or RSD group vs. TC group witiun-diet
comparisons.


grounded on the fact that a number of stressors                 actually decrease tyrosine hydroxylase activity
have been shown to activate tyrosine hydroxylase                (Badawy and Williams, 1982).
activity in the rat brain (Raab and Oswald, 1980),                 Previous investigators have attempted to link a
which is the rate-limiting step for the conversion              large body of sleep deprivation-induced ab-
of tyrosine to DOPA in the synthesis of catechol-               normalities to changes in regulation of central
amines. Normally, this enzymatic reaction is m l y              noradrenergic receptors (Siege1 and Rowgawski,
about 75%saturated with its substrate (cariscon                 1988). However, the importance of noradrenergic
and Lindqvist, 1978). In the absence of stress,                 receptor regulation as mediator of the effects of
exogenously administered tyrosine itself may                    E D has been challenged by the results of
   radioligand binding studies (Tsai et al., 1993).        et a[., 1979; Morden et al., 19681, during which
   Data from our own laboratory suggests that              time dopamine receptor mechanisms may be
   changes in the central norepinephrine concentra-        facilitated, and dopamine D2 receptor stimula-
   tions are more Iikely related to physiological          tion is known to inhibit yawning (Serra et a!.,
  adaptations to methodological stress, rather than        1987). Altering the tyrosine content of the diet
   to a specific effect of RSD (Brock ef at., 1994). I
                                                     n     had no apparent effect on drug-induced yawning
   the present study, it is interesting to note the        in this study.
  distinct absence of an effect by tyrosine supple-           Perhaps the most interesting of the behavioral
  mentation on the effects of watertank-stress (i-e.,      data were the effects of tyrosine supplementation
  the TC group) in all behavioral measures per-            on drug-induced catalepsy. As can be seen in
  formed. This suggests that sleep deprivation, at         Figure 3, both watertank stress and deprivation
  least as it is accomplished using the watertank         of REM deep were associated with significant
  method, may not have the same effect on the             attenuation of cataleptic responses to the dopa-
  noradrenerpc system as that of cold- or shock-          mine Dl receptor agonist SCH23390, in animals
  induced stress, which greatly increase the central      maintained on both control diets. Among the
  release of norepinephrine (Lehnert et a[., 1984;        animials maintained on tyrosine supplementa-
  Weiss et a[., 1981).                                    tion, watertank stress attenuated catalepsy as it
     Hyperphagia, weight-loss, and increased spon-        did in the other diet groups. However, in the
  taneous locomotor activity are perhaps the most         RSD-treated animals consuming 4% tyrosine,
  widely recognized effects of sleep deprivation in       SCH23390 produced a degree of catalepsy that
  rodents (Brock et al., 1994; Everson and Wehr,          was sigruficantly increased, and similar to that of
 1993; Kushlda et al., 19891, even when the sleep         cage control animals on a control diet.
 deprivation is of short-duratiqn. Herein, RSD               Changes in dopamine receptor regulation are
  treatment was associated with a general decrease        among the earliest neurochemical events to occur
 in body weight (Table ILA), increased daily caloric     in the rat brain as a result of RSD (Brock et al.,
 intake (Table ITB), as well as modest increases in      1995; Hamdi et al., 1993). Furthermore, altera-
 spontaneous locomotor activity (Figure 1); how-          tions in dopamine receptor binding in the
 ever, the effects were not as robust as previously       striatum distinguishes between the effects of
seen. Interestingly, dietary supplementation of          RSD and the effects of methodological stress
 tyrosine was associated with a strong fadtation         (Hamdi et al., 1993). Previous studies that
of RSD-induced locomotion, rather than the               revealed a sigrufrcant decrease and increase in
 previously hypothesized mhibition.                      D2dopamine receptor densities in the striatum
     There were significant effects of TC- and RSD-      of TC-treated and RSD-treated rats, respectively
 treatment on drug-induced yawning in the rats           (Hamdi et al., 1993), were reproduced in the
(Figure 2 ) . Being exposed to the watertank alone       present study (Figure 4). Animals maintained on
facilitated this dopamine-mediated behavior,             the normal diet and housed on a large pedestal
whereas sleep deprivation decreased it. This is          with no sleep deprivation (TC group) demon-
consistent with reports by others that rats              strated a sigruficant decrease in the densities of
subjected to 96 h of RSD demonstrate decreased           Dtdopamine receptors when compared to the
yawning behavior in response to a low dose of            cage control (CC) group and the affinity of
apomorphine . (Hipolide and Tufik, 1995;                 radioligand binding increased. On the other
Keumann et al., 1990; T f k et al., 1987). The
                             ui                          hand, following RSD treatment, there was a
mechanism for this may relate to the fact thar           sigruficant increase in the density of Dz dopa-
sleep deprivation results in a state of central          mine receptors, compared with the TC group.
arousal i the subject (Brock et al., 1994; Hicks
           n                                             Among the animal groups maintained on the
                                                   A. HXMDi et al.


   radioiigand binding studies (Tsai et al., 1993).         et al., 1979; Morden et af., 19681, during which
   Data from our own laboratory suggests that               time dopamine receptor mechanisms may be
  changes in the central norepinephrine concentra-          facilitated, and dopamine D2 receptor stimula-
   tions are more likely related to physiological           tion is known to inhibit yawning (Serra et a[.,
  adaptations to methodological stress, rather than         1987). Altering the tyrosine content of the diet
   to a specific effect of RSD (Brock et al., 1994). In     had no apparent effect on drug-induced yawning
   the present study, it is interesting to note the         in this study.
  distinct absence of an effect by tyrosine supple-            Perhaps the most interesting of the behavioral
  mentation on the effects of watertank-stress (i.e.,       data were the effects of tyrosine supplementation
  the TC group) in all behavioral measures per-             on drug-induced catalepsy. As can be seen in
  formed. This suggests that sleep deprivation, at          Figure 3, both watertank stress and deprivation
  least as it is accomplished using the watertank           of REM sleep were associated with significant
  method, may not have the same effect on the              attenuation of cataleptic responses to the dopa-
  noradrenergc system as that of cold- or shock-           mine Dlreceptor agonist SCH23390, in animals
  induced stress, which greatly increase the central       maintained on both control diets. Among the
  release of norepinephrine (Lehnert et al., 1984;         animials maintained on tyrosine supplementa-
 Weiss et al., 1981).                                      tion, watertank stress attenuated catalepsy as it
     Hyperphagia, weight-loss,and increased spon-          did in the other diet groups. However, in the
 taneous locomotor activity are perhaps the most           RSD-treated animals consuming 4% tyrosine,
 widely recognized effects of sleep deprivation in         SCH23390 produced a degree of catalepsy that
 rodents (Brock et al., 1994; Everson and Wehr,            was sigruiicantly increased, and similar to that of
 1993; Kushda et al., 19891, even when the sleep           cage control animals on a control diet.
 deprivation is of short-duratiqn. Herein, RSD                Changes in dopamine receptor regulation are
 treatment was associated with a general decrease          among the earliest neurochernical events to occur
 in body weight (Table IIA),increased daily caloric       in the rat brain as a result of RSD (Brock et al.,
 intake (Table IIB), as well as modest increases in       1995; Hamdi et al., 1993). Furthermore, altera-
 spontaneous locomotor activity (Figure 1);how-            tions in dopamine receptor binding in the
 ever, the effects were not as robust as previously        striatum distinguishes between the effects of
seen. Interestingly, dietary supplementation of           RSD and the effects of methodological stress
 tyrosine was associated with a strong fadtation          (Hamdi et al., 1993). Previous studies that
of RSD-induced locomotion, rather than the                revealed a sigrufrcant decrease and increase in
 previously hypothesized mhibition.                       D2 dopamine receptor densities in the striatum
     There were significant effects of TC- and RSD-       of TC-treated and RSD-treated rats, respectively
treatment on drug-induced yawning in the rats             (Hamdi et al., 1993), were reproduced in the
(Figure 2). Being exposed to the watertank alone          present study (Figure 4). Animals maintained on
facilitated t h s dopamine-mediated behavior,             the normal diet and housed on a large pedestal
whereas sleep deprivation decreased it. This is           with no sleep deprivation (TCgroup) demon-
consistent with reports by others that rats               strated a sigruficant decrease in the densities of
subjected to 96 h of RSD demonstrate decreased            DZ dopamine receptors when compared to the
yawning behavior in response to a low dose of             cage control (CC) group and the affinity of
apomorphine . (Hipolide and Tufik, 1995;                  radioligand binding increased. On the other
Neumann et al., 1990; Tufik et al., 1987). The            hand, following RSD treatment, there was a
mechanism for this may relate to the fact thar            signrficant increase in the density of DZ dopa-
sleep deprivation results in a state of central           mine receptors, compared with the TC group.
arousal in the subject (Brock et al., 1994; ficks         Among the animal groups maintained on the
                    REM SLEEP DEPRIVATION AND DlETARY TYROSINE SUPPLEMENTATION

  valine-supplemented diet, watertank stress was         References
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                                                                                                                     . - . . -- - - .^
                                                                                                                                     . C   .__-____




                                                                      PU
                                                REM SLEEP DEPRIVATION A D DIETARY TYROSINE SWPLEMmA71ON

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                          The dopamine Dl receptor is involved in the regulation of




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