Co-administration of either a selective D1 or D2 dopamine antagonist with methamphetamine prevents methamphetamine-induced behavioral sensitization and neurochemical change, studied by in vivo intracerebral dialysis

Brain Research, 546 (1991) 40-46 © 1991 Elsevier Science Publishers B.V. 0006,8993/91/$03.50 ADONIS 0006899391I6490S

40

BRES 16490

Co-administration of either a selective D 1 o r D 2 dopamine antagonist with methamphetamine prevents methamphetamine-induced behavioral sensitization and neurochemical change, studied by in vivo intracerebral dialysis Takashi Hamamura, Kazufumi Akiyama, Kiyoshi Akimoto, Kenichi Kashihara, Kazuya Okumura, Hiroshi Ujike and Saburo Otsuki Department of Neuropsychiatry, Okayama University Medical School, Okayama (Japan) (Accepted 30 October 1990)

Key words: Methamphetamine; SCH 23390; YM-09151-2;Dopamine release; Reverse tolerance; Dialysis

Repeated administration of amphetamine or methamphetamine (MAP) causes behavioral sensitization in animals. Recently, several studies have revealed that in vivo release of dopamine from presynaptic nerve terminals of mesotelencephalic dopamine neurons is enhanced when sensitized animals are rechallenged with a psychostimulant. The present study investigated the effect of co-administration of SCH 23390 (a selective D 1 dopamine receptor antagonist) or YM-09151-2 (a selective D2 dopamine receptor antagonist) prior to each MAP injection for 14 days on dopamine effiux in the striatal perfusates using in vivo dialysis. After 3 months drug abstinence, MAP challenge alone produced augmented stereotypy in the MAP group, but not in the control, the SCH 23390 + MAP or the YM-09151-2 + MAP group. In parallel with this behavioral observation, the degree to which dopamine effiux increased following the MAP challenge was significantly greater in the MAP group than that in the control, SCH 23390 + MAP group and the YM-09151-2 + MAP groups. While dopamine efflux after MAP ehall~nge did not differ between the control and the YM-09151-2 + MAP group, it was greater in the SCH 23390 + MAP group than the control group. These results indicate that both D 1 and D 2 dopamine receptors play a role in the formation of behavioral sensitization, but with different mechanisms. INTRODUCTION

is enhanced when sensitized rats are re-challenged with a psychostimulant8,16,2°,23,31,32,34. While these studies sug-

Methamphetamine (MAP) injection causes behavioral activation and euphoric effects. However, abuse of MAP leads to psychotic symptoms which are virtually indistinguishable from those of paranoid schizophrenia 4'5'1°. This chronological change in the clinical features of the MAP response suggests an evolution of brain dysfunction which is progressively produced by repetition of MAP use. Once developed, MAP-induced paranoid state readily recurs with a low dose of MAP-reuse even after longterm abstinence. Thus the supposed brain dysfunction seemed to be long-lasting36'37. In animal studies, repeated administration of MAP causes a progressive augmentation of locomotion and stereotyped behavior. Thus this MAP-induced behavioral sensitization has been well established as an animal model of schizophrenia 33'3s. Several lines of evidence have revealed that release of dopamine from presynaptic nerve terminals of mesotelencephalic dopamine neurons

gest that presynaptic change plays an important role:in behavioral sensitization, the mechanism underlying the development of this presynaptic change has not yet been elucidated. In behavioral studies, haloperid01 prevents MAP or amphetamine-induced behavioral sensitization, thus dopaminergic transmission has been supposed t o be necessary to the development of behavioral sensitization 19'24. We previously demonstrated that co-administration of either SCH 23390 (a selective dopamine D1 receptor antagonist) or YM-09151-2 (a selective dopamine D 2 receptor antagonist) prior to each MAP injection not only blocked acute behavioral effects of M A P at each injection but also prevented the development of behavioral sensitization induced by repeated MAP administrations 4°. Thus we assumed that both D 1 and D2 dopamine receptors may be involved in the development of MAP-induced behavioral sensitization. In the present study, in order to investigate the

Correspondence: Takashi Hamamura, Department of Neuropsychiatry,Okayama University Medical School, 2-5-1 Shikata-cho, Okayama, 700 Japan.

41 pharmacological basis of our previous report, we examined the prophylactic effect of SCH 23390 and YM09151-2 on MAP-induced behavioral sensitization and associated enhanced dopaminergic transmission during MAP re-challenge after long-term drug abstinence using in vivo microdialysis. In this study we examined extracellular dopamine and its metabolites in rat striatum as an index of dopaminergic transmission since striatal dopaminergic transmission has been reported to play an important role in stereotypy 21. MATERIALS AND METHODS

HPLC-ECD system (IRICA Co., Kyoto, Japan) for measurement of dopamine, DOPAC and HVA. These compounds are separated at 27 °C by ion-pair reverse-phase chromatography using a 5-/~m Cosmosil ODS-C18 resin (Nakarai Co., Kyoto, Japan) and a mobile phase consisting of 0.05 M sodium dihydrogen phosphate buffer (pH 4.3) containing EDTA (0.05 mM), octanesulfonic acid (1 mM), 5% methanol and 5% acetone. The glassy carbon working electrode was set at +700 mV. The mean of 3 samples immediately before the drug injection was regarded as the zero time value, and the changes in levels of extracellular dopamine, DOPAC and HVA were expressed as a percentage of the zero time value. After completion of the experiments, the position of each probe was checked histologically. Statistical analysis of data were carried out using the Kruskal-Wallis analysis of variance, Mann-Whitney U-test for behavioral experiments, the one-way ANOVA for the basal value of DA and its metabolites and two-way ANOVA for change of DA and its metabolite after MAP injection.

Materials and pretreatment regimen Male Sprague-Dawley rats weighing 260-280 g at the start of treatment were housed with free access to food and water under a 12 h light-12 h dark cycle (lights on at 6.00 h). Experiment 1. Eighteen rats were divided into 3 groups of six. MAP group: rats were intraperitoneally injected once daily with MAP (4 mg/kg) for the first 7 consecutive days, and MAP (8 mg/kg) for the next 7 consecutive days. This escalating dose established definite behavioral sensitization. SCH + MAP group: rats were pretreated with SCH 23390 (0.5 mg/kg s.c.) 5 min prior to each MAP injection for 14 consecutive days. MAP was injected in the same manner as in the MAP group. Control group: rats were injected with saline (1 ml/kg i.p.) for 14 days. Experiment 2. Twenty-four rats were divided into 3 groups of eight. These consisted of MAP, YM + MAP and control groups. In these groups, drug administration schedules were the same as in Expt. 1 except for the YM + MAP group where YM-09151-2 (1 mg/kg i.p.) was substituted for SCH 23390. It was demonstrated that this co-administration schedule of SCH 23390 and YM-09151-2 with MAP was enough to block MAP-induced behaviors4°. Both injection of SCH 23390 (0.5 mg/kg) and YM-09151-2 (1 mg/kg) induced catalepsy, whereas after MAP injection rats exhibited stage 0 behavior without catalepsy. MAP, SCH 23390 and YM-09151 were dissolved in saline.

RESULTS

Behavior Expt. 1. After an abstinence period of 3 months, a (a) 4 LIJ I:E

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Behavior rating and in vivo dialysis procedure after MAP challenge Three months after the last drug injection, rats were anesthetized with pentobarbital (50 mg/kg i.p.) and placed in a stereotaxic frame. The skull was exposed and a hole was drilled for the implantation of a dialysis probe into the anterior striatum (coordinates: rostral +2.4 mm, lateral +3.0 mm, ventral -6.0 ram, from the bregma and the dura surface) according to the atlas of Pellegrino and Cushman 29. The probe was implanted and secured with dental cement and skull screws. The dialysis probe was made of ethylene vinyl alcohol plasmapheresis tubing (Evaflux A2,200/~n diameter, Kurare Co., Osaka, Japan) as described in detail elsewhere 13. Dialysis experiments were begun 18 h after the implantation. The dialysis probe was continuously perfused at 2 ktl/min with physiological Ringer solution (Na + 147 mM, K ÷ 4 mM, Ca z+ 2.25 mM, CI 155.5 mM, pH 6.5), and perfusates were collected every 20 min. After a 3-h habituation period, the rats were injected with MAP (4 mg/kg i.p.). Behavioral assessment was conducted for 60 min, and the intensity of stereotypy was estimated at 10, 15, 20, 30, 40 and 60 min after the administration according to the rating scale of Akiyama et al.Z: 0, asleep or still; 1, locomotion with normal exploration and normal pattern of sniffing; 2, hyper-locomotion with repetitive exploratory behavior, rearing or increased rate of sniffing; 3, discontinuous sniffing with periodic locomotion activity; 4, continuous compulsive sniffing without locomotion. Striatal extracellular concentrations of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured for 3 h after the administration. The perfusates were injected directly into a reverse-phase ion-pair

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Fig. 1. Effect of SCH 23390 (a) and YM-09151-2 (b) on behavioral sensitization to MAP. Following chronic administration session, each group received a challenge dose of 4 mg/kg methamphetamine (MAP) at 3 months after drug abstinence. Rats received repeated injection of saline (O), MAP (O), 0.5 mg/kg SCH 23390 plus MAP (11), 1 mg/kg YM-09151-2 plus MAP (A) respectively. Data represent mean _+ S.E.M. for group of 6 rats in Fig. la and 8 rats in Fig. lb *P < 0.05, **P < 0.01 saline group versus others (KruskaI-Wallis test and Mann-Whitney U-test).

42 challenge dose of 4 mg/kg M A P p r o d u c e d locomotion and s t e r e o t y p y consisting of sniffing and r e p e a t e d head m o v e m e n t s . A t 10, 15 and 20 min after the injection, rats in the M A P group exhibited focused stereotypy which was significantly m o r e intense than in the control group (Fig. l a ) . T h e r e was no significant difference in the intensity of s t e r e o t y p y b e t w e e n the S C H + M A P group and the control group. Expt. 2. A t 10, 15, 20 and 30 min after injection, rats in the M A P group exhibited focused s t e r e o t y p y which was significantly m o r e intense than that in the control group (Fig. l b ) . T h e r e was no significant difference in the intensity of s t e r e o t y p y between the Y M + M A P group and the control group. These results indicate that r e p e a t e d M A P injections induced long-lasting behavioral sensitization and that p r e t r e a t m e n t of S C H 23390 or YM-09151-2 c o m p l e t e l y p r e v e n t e d the d e v e l o p m e n t of M A P - i n d u c e d behavioral sensitization.

Extracellular dopamine and its metabolites Expt. 1. A f t e r M A P challenge, the striatal extracellular d o p a m i n e level increased and the maximal change was o b s e r v e d in perfusates collected at 20-40 rain (Fig. 2). The maximal levels were 493 _+ 63% (mean __ S . E . M . ) in the M A P group, 453 _+ 47% (mean _+ S . E . M . ) in the S C H + M A P group and 350 _+ 63% (mean _+ S . E . M . ) in

the control group. In the M A P group the increase in extraceUular d o p a m i n e levels was significantly greater than in the control group (effect of p r e t r e a t m e n t , F~,9o = 47.494 P < 0.01; effect of time, F8.90 = 29.264 P < 0.01; p r e t r e a t m e n t x time interaction, Fs,9o = 1.754 n.s,). In the M A P group the increase in extracellular d o p a m i n e levels was also significantly g r e a t e r than in the S C H + M A P group (effect of p r e t r e a t m e n t , F1,9o = 23.551 P < 0.01; effect of time, Fs,9o = 32.940 P < 0:01; pretreatment x time interaction, F8,90 = 1.245 n.s,). T h e r e was a greater, albeit subtle, increase in extracellular dopamine level in the S C H + M A P group than the control group (effect of p r e t r e a t m e n t , k'190 = 3.9902 P < 0,05; effect of time, F8,9o = 29.070 P < 0.01; p r e t r e a t m e n t x time interaction, F8,90 = 0.671 n.s,). W h i l e extraceUular levels of D O P A C and H V A d e c r e a s e d after the M A P challenge, there was no significant difference in the degree to which both m e t a b o l i t e s d e c r e a s e d a m o n g the 3 groups (Fig. 3). In basal extracellular levels of d o p a m i n e ,

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Fig. 2. Effects of chronic co-administration of SCH 23390 with MAP: extracellular dopamine level in striatal perfusates after MAP injection. Following chronic administration session, each group received a challenge dose of 4 mg/kg MAP at 3 months after drug abstinence. See Fig. la legend for meanings of symbols. In the MAP group the increase in the extraeellular dopamine level was significantly greater than the control group F1.9o = 47.494 P < 0.01, or the SCH + MAP group F | , 9 o = 23.551 P < 0.01. The means + S.E.M. are shown and the values are given as percent of zero time value. The 100% value for DA were for the saline control 134 +_ 21.9 fmol/40 pl; for the MAP pretreated group, 116 + 15.7 fmol/40 pl, for the SCH + MAP pretreated group, 129 + 10.5 fmol/40 pl.

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Fig. 4. Effects of chronic co-administration of YM-09151-2 with MAP: extracellular dopamine level in striatal perfusates after MAP

injection. Following chronic administration session, each group received a challenge dose of 4 mg/kg MAP at 3 months after drug abstinence. See Fig. lb legend for meanings of symbols. In the MAP group the increase in the extracellular dopamine level was significantly greater than the control group (Fl.12 6 = 19.086, P < 0.01) or the YM + MAP group (F1.126 = 25.628, P < 0.01). The means + S.E.M. are shown and the values are given as percent of zero time value. The 100% value for dopamine were for the saline control 149 _+ 19.0 fmol/40 ~ul; for the MAP pretreated group, 140 + 16.7 fmol/40 ktl; for the YM + MAP pretreated group, 147 + 16.9 fmol/40 ,ul.

D O P A C and HVA, there were no significant differences in the 3 groups. Expt. 2. After M A P challenge, striatal extracellular dopamine levels increased and the maximal change was observed in perfusates collected at 20-40 min (Fig. 4). The maximal levels were 463 _+ 52% (mean _+ S.E.M.) in the M A P group, 328 _+ 36% (mean _+ S.E.M.) in the YM + M A P group, 338 _+ 47% (mean __ S.E.M.) in the control group. In the M A P group the increase in the extracellular dopamine level was significantly greater than in the control group (effect of pretreatment, El,12 6 = 19.086 P < 0.01; effect of time, F 8 , 1 2 6 = 24,220 P < 0.01; p r e t r e a t m e n t x time interaction, F 8 , 1 2 6 = 1.603 n.s.). In the M A P group the increase in the extracellular dopamine level was also significantly greater than in the YM + M A P group (effect of pretreatment F1,126 = 25.628 P < 0.01; effect of time, Fs.126 = 23.938 P < 0.01; pretreatment x time interaction, F 8 , 1 2 6 = 1.201 n.s.). There was no significant difference in the extracellular dopamine level between the YM + M A P and the control group. While extracellular levels of D O P A C and H V A decreased after the M A P challenge, there was no significant difference in the degree to which both metabolites decreased among the 3 groups (Fig. 5). In basal extracellular levels of dopamine, D O P A C and HVA, there were no significant differences in the 3 groups.

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perfusates after MAP injection. Following chronic administration session, each group received a challenge dose of 4 mg/kg MAP at three months after drug abstinence. See Fig. lb legend for meanings of symbols. The means + S.E.M. are shown and the values are given as percent of zero time value. The 100% value for DOPAC and HVA were for the saline control, 29.3 + 3.87 pmol/40 ktl and 26.4 _+_2.08 pmol/40/A; for the MAP pretreated group, 26.9 + 1.25 pmol/40 ktl and 27.4 + 2.20 pmol/40 ffl; for the YM + MAP pretreated group, 26.2 + 1.67 pmol/40 gl and 26.4 + 1.78 pmol/40 ktl.

DISCUSSION

The present study revealed that M A P - i n d u c e d behavioral sensitization was m a i n t a i n e d long-lasting for 3 months abstinence. This behavioral sensitization was accompanied by enhanced elevation of extracellular dopamine levels after M A P challenge though basal levels remained the same. However there were some differences in the time course between behavior and extracellular dopamine levels. It may be because the challenge dose of 4 mg/kg M A P was so large for a behavioral study that the behavioral rating score reached maximal easily, and then gave rise to such a difference in the time course. These data may confirm our previous report in which the greater increase in d o p a m i n e release was observed in parallel with intense stereotypy following a M A P challenge after a drug abstinence period of one week 2°. Furthermore, the significance of long-lasting susceptibility to enhanced d o p a m i n e release as well as of intense stereotypy should be stressed since such long-lasting

44 susceptibility is widely recognized in MAP abusers in

clinical studies 36,37. In agreement with our present and previous report, several studies have indicated that the enhanced release of dopamine from presynaptic nerve terminals is neurochemical alteration underlying the re-challenge-induced manifestation of behavioral sensitization. In vitro studies using striatal slices also showed that amphetamine (AMP) or MAP pretreatment enhances dopamine release after the challenge of these drugs 8'23'31"32'43. Using in vivo dialysis, Robinson et al. 34 reported that AMP pretreatment enhanced dopamine release in the nucleus accumbens after an AMP challenge. While there are topographical differences (nucleus accumbens vs striatum) between their results and our present and previous data, they are of the same view that an enhanced sensitivity of dopaminergic presynapses to AMP or MAP challenge plays an important role in the pharmacological basis of behavioral sensitization. Although the precise mechanism responsible for this presynaptic change is not yet known, several hypotheses have been presented. Castafieda et al. 8 proposed that dopamine-containing vesicles in presynaptic nerve terminals might be shifted to a more releasable state in sensitized rats. On the other hand, we recently reported that MAP-pretreated rats exhibit intense behavioral responses and enhanced increases in striatal extracellular dopamine levels over controls after a challenge with cocaine ~. This result indicates that the function of dopamine uptake sites on which cocaine acts may somehow be changed during repeated MAP injections and may lead to an enhanced dopamine release in 'cross reverse tolerance' between MAP and cocaine 37. Concerning the mechanism underlying the development of behavioral sensitization, we recently reported that co-administration of SCH 23390 or YM-09151-2 prevents the development of MAP-induced behavioral sensitization 4°. Recently, Vezina et al. 42 reported that co-administration of SCH 23390 but neither pimozide nor Ro 22-2586, D z antagonists, prevent AMP-induced behavioral sensitization. This discrepancy may be due to the dose of AMP or MAP used. Thus we used moderate dose of MAP and behavioral sensitization was estimated by stereotyped behavior. On the other hand Vezina et al. 42 used low dose of AMP, 1 mg/kg for pretreatment, 0.5 mg/kg for a challenge test and behavioral sensitization was estimated by locomotor activity. We suppose there are different mechanisms in behavioral sensitization induced by the two different doses, but further study is necessary to clarify this hypothesis, To investigate the pharmacological basis of our previous study, we examined the effects of SCH 23390 or YM-09151-2 co-administration prior to each MAP injec-

tion on the development of a MAP-rechallenge-induced enhanced dopamine efflux in striatal perfusates. The results suggest that a blockade of each subtype of dopamine receptor during chronic MAP administration suppresses the development of presynaptic change, although the manner by which such prophylactic effects occurred might differ between the two antagonists. Thus, while the apparent preventive effect of the two antagonists against the development of behavioral sensitization was confirmed; enhanced dopamine effiux in the striatal perfusates following MAP challenge was completely prevented by co-administration of YM-09151-2, but only partially suppressed by co-administration of SCH 23390. The explanation for these results seems to be complex. D 2 receptors of mesotelencephalic dopamine neurons are located on post- and presynaptic sites in the striatum, and on somatodendritic sites in substantia nigra pars compacta (SNc) 11'25"26. Presynaptic D 2 receptor in the striatum regulates the release and synthesis of dopamine, and in the SNc, modulates the firing rates of dopamine cells 9A5'27'35. On the other hand, in the striatum, stimulation of postsynaptic D 2 receptor by released endogenous dopamine was related to the behavioral effect of MAP, since local injection of a neuroleptic into the striatum reversed MAP-induced behavior 3°, Thus we speculate that co-administration of YM-09151-2 with each MAP injection completely blocked the effect of MAP on D 2 receptors both at nigrostriatal dopamine neurons and postsynaptic sites, therefore preventing the development of both behavioral and presynaptic sensitivity. There is no evidence that D~ receptors are located on nigrostriatal dopamine neurons 3'26"2s. Systemic injection of SCH 23390 causes a minimal effect on dopaminergic activity and this effect is thought to be mediated via long-loop feedback from striatal postsynaptic D 1 receptors 6~7"14'17'44. So it is unlikely that SCH 23390 would exert a direct effect against MAP on nigrostriatal dopaminergic neurons. D l dopamine receptors are distributed on the substantia nigra zona reticulata (SNr), postsynaptic non dopaminergic cells in the striatum, entopeduncular nucleus and frontal cortex at high density 12"22. These structures are connected by a neuronal projection to make a neuronal circuit. D~ receptors are known to exist on striatonigral nerve terminals in SNr 3. Recently, Kalivas et al.t8 reported that repeated microinjection of amphetamine into A10 or A9 produced behavioral sensitization. Stewart et al. 39 demonstrated that microinjection of SCH 23390 into the ventral tegmental area or into the SNr attenuated the development of sensitization to the repeated systemic injection of amphetamine. Ujike et al. 41 demonstrated that repeated MAP treatment results in an increase in D~ receptors labeled with

45 [3H]SCH 23390 in the lateral portion of the SNr. These

lenge, but co-administration of SCH 23390 completely

results indicate that the prophylactic effect of SCH 23390

suppressed behavioral sensitization but only partially

on behavioral sensitization is not exerted directly in nigrostriatal dopaminergic neurons, but in other neuronal

prevented dopaminergic hyper-sensitivity. These results

circuits such as the SNr. In conclusion, the present study demonstrated that e n h a n c e d dopamine release in response to a M A P challenge to previously sensitized rats occurs after 3

indicate that some plastic change in transsynaptic neuronal circuits occur during the development of behavioral sensitization and that D 1 and D 2 antagonists prevent the development of behavioral sensitization via different mechanisms. Further studies are necessary to identify the

months of abstinence, suggesting that this long-lasting

neural circuit or brain area responsible for behavioral

neurochemical alteration is associated with behavioral sensitization. The present study also showed that coadministration of YM-09151-2 with each M A P injection

sensitization.

completely suppressed both behavioral sensitization and the enhanced dopamine release, following M A P chalREFERENCES 1 Akimoto, K., Hamamura, T., Kazahaya, Y., Akiyama, K. and Otsuki, S., Enhanced extracellular dopamine level may be the fundamental neuropharmacological basis of cross-behavioral sensitization between methamphetamine and cocaine - - an in vivo dialysis study in freely moving rats, Brain Research, 507 (1990) 344-346. 2 Akiyama, K., Sato, M. and Otsuki, S., Increased [3H]spiperone binding sites in mesolimbic area related to methamphetamineinduced behavioral hypersensitivity, Biol, Psychiatry, 17 (1982) 223-231. 3 Altar, C.A. and Hauser, K., Topography of substantia nigra innervation by D~ receptor-containing striatal neurons, Brain Research, 410 (1987) 1-11. 4 Angrist, B., Lee, H.K. and Gershon, S., The antagonism of amphetamine-induced symptomatology by a neuroleptic, Am. J. Psychiatry, 131 (1974) 817-819. 5 Bell, D.S., The experimental reproduction of amphetamine psychosis, Arch. Gen. Psychiatry, 29 (1973) 35-40. 6 Boyar, W.C. and Altar, C.A., Modulation of in vivo dopamine release by D2 but not D~ receptor agonist and antagonists, J. Neurochern., 48 (1987) 824-831. 7 Carlson, J.H., Bergstrom, D.A. and Waiters, J.R., Neurophysiological evidence that D~ dopamine receptor blockade attenuates postsynaptic but not autoreceptor-mediated effects of dopamine agonists, Eur. J. Pharmacol., 23 (1986) 237-251. 8 Castafieda, E., Becker, J.B. and Robinson, T.E., The long-term effects of repeated amphetamine treatment in vivo on amphetamine, KCI and electrical stimulation evoked striatal dopamine release in vitro, Life Sci., 42 (1988) 2447-2456. 9 Cheramy, A., Leviel, V. and Glowinkski, J., Dendritic release of dopamine in the substantia nigra, Nature, 289 (1981) 537-542. 10 Ellinwood, E.H., Sudilovsky, A. and Nelson, L.M., Evolving behavior in the clinical and experimental amphetamine (model) psychosis, Am. J. Psychiatry, 130 (1973) 1088-1093. 11 Filloux, M.E, Wamsley, J.K. and Dawson, T.M., Dopamine D 2 auto- and postsynaptic receptors in the nigrostriatal system of the rat brain: localization by quantitative autoradiography with [3H]sulpiride, Eur. J. Pharmacol., 138 (1987) 61-68. 12 Fuxe, K., Cintra, A., Agnati, L.E, H~rfstrand, A. and Goldstein, M., Studies on the relationship of tyrosine hydroxylase, dopamine and cyclic AMP-regulated phosphoprotein-32 immunoreactive neuronal structures and O 1 receptor antagonist binding sites in various brain regions of the male rat - mismatches indicate a role of D~ receptors in volume transmission, Neurochem. Int., 13 (1988) 179-197. 13 Hamamura, T., Kazahaya, Y. and Otsuki, S., Ceruletide suppresses endogenous dopamine release via vagal afferent system, studied by intracerebral dialysis, Brain Research, 483

Acknowledgements. This work was supported by grants from Biological Study of Schizophrenia from the Ministry of Health and Welfare, and from Biological Study of Drug-dependence from Science and Technology Agency.

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