Brain Research, 540 (1991) 159-163 Elsevier
159
BRES 16283
Lasting increase in D 1 dopamine receptors in the lateral part of the substantia nigra pars reticulata after subchronic methamphetamine administration Hiroshi Ujike, Kazufumi Akiyama, Hiroshi Nishikawa, Taichi Onoue and Saburo Otsuki Department of Neuropsychiatry, Okayama University Medical School, Okayama 700 (Japan) (Accepted 21 August 1990)
Key words: Methamphetamine; D:receptor; Dopamine receptor; [3H]SCH23390; Substantia nigra pars reticulata; Behavioral sensitization
To examine the possible involvement of D 1dopamine receptors in behavioral sensitization induced by subchronic methamphetamine (MAP) administration, regional D1 receptors labeled with [3H]SCH 23390 were examined using binding assay and quantitative autoradiography. Rats received 4 mg/kg/day MAP (i.p.) for 14 days, and were decapitated after an abstinence period of 24 h, 7 days or 21 days. In MAP-treated rats, a significant decrease in Kd in the mesolimbic area was observed 24 h but not 7 days after the last injection. Neither Kd nor B~ax changed in the striatum or medial prefrontal cortex of MAP-treated rats after any period of abstinence. Autoradiography revealed a significant increase in specific [3H]SCH 22390 binding in the lateral part of the substantia nigra pars reticulata (SNr) of MAP-treated rats. Since this increase lasted up to 21 days after cessation of subchronic MAP administration, it is suggested that lasting increase in the nigral D 1receptors may be associated with the biological changes underlying MAP-induced behavioral sensitization.
INTRODUCTION Repeated administration of amphetamine (AMP) or methamphetamine (MAP) to animals produces augmentation of hyperlocomotion and stereotyped behavior 21' 24,33 Such behavioral sensitization or reverse tolerance has been widely established as an animal model for AMP or MAP psychosis and paranoid-type schizophrenia in humans 12'3°'34. Thus an analogy between behavioral sensitization in animals and the clinical features of AMP or MAP psychosis is characterized by progressive augmentation with repeated administration (chronological change) and an irreversible susceptibility to recurrence in response to re-use of these psychostimulants (lasting susceptibility). Recent neurochemical studies using in vivo intracerebral dialysis, including that of the authors, have demonstrated that dopamine release is enhanced in the striatum and nucleus accumbens when AMP or MAP is rechallenged to previously sensitized animals 2°'3~. Furthermore, this enhanced dopamine release has also been shown upon re-challenge of MAP to animals sensitized by chronic cocaine 1. These findings indicate that enhanced release of dopamine may underlie the neurochemical mechanism in both MAP-induced behavioral sensitization and cross-sensitization between MAP and cocaine.
It has been shown that MAP-induced sensitization can be blocked by co-administration of haloperidot, a D1/D 2 mixed dopamine antagonist 19. We also demonstrated that co-administration of either SCH 23390 (a selective D 1 antagonist) or YM-09151-2 (a selective D 2 antagonist 37' 38) prior to each MAP injection not only blocked the acute effect of MAP but also prevented the development of behavioral sensitization 4°. In addition, we recently showed that such treatments with selective D 1 and D 2 antagonists also prevented the neurochemical changes resulting in enhanced dopamine release from the sensitized striatum 14. This prevention by D 1 antagonist of sensitization in both behavior and striatal dopamine releasability appears to be important in light of the fact that a D 1 antagonist could be applicable as a new antipsychotic drug with an ability to suppress conditioned avoidance response and to produce catalepsy 9'15. Furthermore, these findings indicate that D1 receptor may also be involved in the therapeutic effects of neuroleptics and in the pathogenesis of psychostimulant-induced sensitization. To clarify this possibility, the present study investigated regional changes in D~ receptors labeled with [3H]SCH 23390 in the rat brain after MAP-induced sensitization using a binding assay and quantitative autoradiography.
Correspondence: H. Ujike, Dept. of Neuropsychiatry, Okayama Univ. Med. School, 2-5-1 Shikata-cho, Okayama 700, Japan. 0006-8993/91/$03.50 © 1991 Elsevier Science Publishers B.V. (Biomedical Division)
160 MATERIALS AND METHODS Male Sprague-Dawley rats weighing 200-220 g at the beginning of drug administration were used. The animals were group-housed, with free access to food and water, at constant temperature (24 °C) and humidity (65%) under a standard 12-12-h light-dark cycle (lights on at 07.00 h). The rats received intraperitoneal (i.p.) injections of either 4 mg/kg MAP or saline once daily for 14 consecutive days. We had previously confirmed that this MAP administration schedule resulted in behavioral sensitization4°. MAP-treated rats were decapitated after 3 different abstinence periods of 24 h, 7 days or 21 days (MAP-24h, MAP-7d or MAP-21d group). Saline-treated rats were decapitated after an abstinence period of 24 h or 21 days (control-1 or control-2 group). The brain was rapidly removed, and the medial prefrontal cortex, striatum and mesolimbic area consisting of the nucleus accumbens and olfactory tubercle were dissected out on ice and stored below -80 °C until [3H]SCH 23390 binding assay. The remaining midbrain including the substantia nigra was embedded in O.C.T. compound and quickly frozen in dry ice-acetone. Coronal sections of rat brain (20pm thick, level AP: -5.3 mm, according to the atlas of Paxinos and Watson z6) were prepared using a coldtom (Sakura Seiki Co. CM-41) at -20 °C and thaw-mounted on gelatin/chrome alum-coated slides. These sections were stored at -20 °C until use. Binding assay The tissue was homogenized in 100 vols. of ice-cold 50 mM Tris-HCl buffer (pH 7.4) and centrifuged at 30,000 g for 10 min. This step was repeated 3 times and the final pellet was resuspended in 50 mM Tris-HC1 buffer (pH 7.4) containing 120 mM NaCI, 5 mM KCI, 2 mM CaCI 2 and 1 mM MgCI~. Aliquots of 100/A of membrane suspension were incubated in triplicate with [3H]SCH 23390 (spec. act. 71.3 Ci/mmol, New England Nuclear) at various concentrations of 0.05-8 nM in a final volume of 1 ml at room temperature for 60 min. Non-specific binding was determined in the presence of 10 ~M unlabeled SCH 23390 (Schering Co. U.S.A.). After incubation, the contents were immediately filtrated under reduced pressure through Whatman GF/B filters which had been presoaked in 0.1% polyethylenimine for 3 h. The filters were rinsed 3 times each with 5 ml of ice-cold 50 mM Tris-HCl buffer. Specific binding, which was calculated by subtracting the non-specific binding from total binding, was usually 90% of the total binding. Protein concentration was measured using a Bio-Rad protein assay kit. A utoradiography The frozen slide-mounted sections were thawed and preincubated in 50 mM Tris-HCl buffer (pH 7.4) containing the same salts as in the binding assay buffer for 15 min at room temperature. They were then transferred to incubation buffer containing 1 nM [3H]SCH 23390, and were incubated for 60 min at room temperature. Adjacent sections were incubated with 1 nM [3H]SCH 23390 in the presence of 1 /~M unlabeled SCH 23390 to determine the nonspecific binding. The incubations were terminated by 4 × 2 min washes in ice-cold 50 mM Tris-HCl buffer, and dipped in ice-cold distilled water. The slides were rapidly dried under a cool air stream, and exposed to a sheet of tritium-sensitive Ultrafilm (L.K.B. Co.) in X-ray cassettes at 4 °C for 1 week. [3H]Microscale (Amersham Co.) was co-exposed to the film as a standard. The films were developed in Kodak D-19 developer. Autoradiographic pictures obtained were analyzed with a computer-assisted imageanalyzer (Olympus CIA-10 system) for quantification of binding density. To avoid possible bias during autoradiography, samples of MAP-treated groups and their control groups were simultaneously incubated in the same baths and were exposed to the same films. Statistical analyses were performed by a one-way ANOVA followed by two-tailed Student's t-test when comparing among control-I, MAP-24h and MAP-7d, and by Student's t-test when comparing between control-2 and MAP-21d.
RESULTS Scatchard
analysis
of
the
saturation
isotherm
of
[ 3 H ] S C H 23390 i n d i c a t e d a single p o p u l a t i o n o f b i n d i n g sites in t h e t h r e e
brain regions examined.
In M A P -
t r e a t e d rats, a s i g n i f i c a n t d e c r e a s e in K,t of a b o u t 2 0 % was o b s e r v e d in t h e m e s o l i m b i c a r e a 24 h a f t e r t h e last i n j e c t i o n ( T a b l e I, F2,19 = 3.7879, P < 0.05 b y o n e - w a y ANOVA,
a n d P < 0.05 b y S t u d e n t ' s t-test). H o w e v e r ,
t h e K d r e c o v e r e d t o t h e c o n t r o l level w i t h i n 7 days. T h e r e w a s n o c h a n g e in Bma x in t h e m e s o l i m b i c a r e a . N e i t h e r Ko n o r Bm~ × c h a n g e d in t h e s t r i a t u m o r m e d i a l p r e f r o n t a l cortex of MAP-treated
rats a f t e r a n y p e r i o d of absti-
nence. Autoradiography
of
D1
receptors
labeled
with
[ 3 H ] S C H 23390 in t h e s u b s t a n t i a n i g r a p a r s r e t i c u l a t a ( S N r ) r e v e a l e d t h a t t h e r e was a g r a d i e n t d i s t r i b u t i o n o f D 1 r e c e p t o r s w i t h a h i g h e r d e n s i t y in t h e m e d i a l p a r t o f t h e S N r t h a n in t h e l a t e r a l p a r t (Fig. 1). S u c h a g r a d i e n t d i s t r i b u t i o n o f n i g r a l D 1 r e c e p t o r s is c o n s i s t e n t w i t h t h e findings of the previous
s t u d y 3. T h e r e f o r e ,
[3H]SCH
23390 b i n d i n g was m e a s u r e d s e p a r a t e l y in t w o s u b r e g i o n s of t h e m e d i a l a n d l a t e r a l SNr. [ 3 H ] S C H 23390 b i n d i n g s i g n i f i c a n t l y i n c r e a s e d b y 2 3 % ( P < 0.05) a n d 3 5 % ( P < 0.01) in t h e l a t e r a l S N r o f M A P - t r e a t e d
r a t s 24 h a n d 7
d a y s a f t e r t h e last i n j e c t i o n , r e s p e c t i v e l y ( T a b l e II, /~,ls
TABLE I Scatchard analysis o f [3H]SCH 23390 in regional brain after subchronic methamphetamine administration Rats received either saline or 4 mg/kg of methamphetamine (MAP) for 14 consecutive days, and then, were decapitated after an abstinence period of 24 h (control-l, MAP-24h group), 7 days (MAP-7d group) or 21 days (control-2, MAP-21d group). Means ± S.D., n = 7-8. K j (nM)
B m,~ (fmot/mg protein)
Striatum Control-I MAP-24 h MAP-7d
0.358 + 0.060 0.335 + 0.036 0.379 + 0.090
3007.3 + 591.3 3092.2 + 651.7 3202.5 + 657.2
Control-2 MAP-21 d
0.443 -+-0.073 0.407 ± 0.043
4201.3 + 743.9 4192.8 -+ 693.8
0.477 ± 0.090 0.396 +0.028" 0.405 ± 0.073
1848.8 ± 140,7 2039.7 ± 71.5 I917.4 _+ 189.1
0.586 ± 0.138 0.679 -+ 0.178
1426.8 -+ 239.6 1376.8 -+ 510.0
0.888 ± (/.269 (I.72(I ± (I.218
294.1 + 37.5 309.4 ± 7(I.6
Mesolimbic area Control-I MAP-24h MAP-7d Control-2 MAP-21d Medial frontal cortex Control- 1 MAP-7d
~'P < 0.05 compared with control group.
161 DISCUSSION
Fig. 1. Autography of substantia nigra using [3H]SCH23390. Notice the higher density ot lateral nigra pars reticulata of MAP-24d and MAP-7d groups than that of control-1 group. Bar = 1 mm.
= 6.2310, P < 0.01 by one-way ANOVA, P < 0.05 and P < 0.01 by Student's t-test between control-1 and MAP-24h, and between control-1 and MAP-7d group, respectively). A similar tendency of an increase by 22% in DI binding in the lateral SNr was observed even after a 21-day abstinence period
TABLE II [~H]SCH 23390 binding in two subregions of substantia nigra pars reticulata measured by quantitative autoradiography
See the legend of Table I for the meaning of groups. Means + S.D, n = 7-8. SNr-specific binding (fmol/mg tissue) Medial
Lateral
Control-1 MAP-24h MAP-7d
303.7 + 48.8 332.7 + 37.5 332.8 + 30.0
211.3 + 50.3 261.5 + 34.3b 285.2 + 34.7a
Control-2 MAP-21d
352.2 + 23.5 379.8 + 43.2
243.2 + 30.7 297.3 + 52.1c
~P < 0.01, bp < 0.05 compared with control-1 group, and cp < 0.1 compared with control-2 group.
The present study is the first to demonstrate a significant increase in [3H]SCH 23390 binding in the lateral part of the SNr which was maintained for 21 days after cessation of MAP administration. This lasting increase in D1 receptors in the SNr is intriguing in the light of our previous reports 14'4° on the effect of D 1 antagonist on the development of behavioral sensitization and accompanying dopamine releasibility. Thus, intense stereotypy, which was otherwise induced by a MAP challenge after sensitization, was abolished in the animals that were co-administered SCH 23390 with MAP. In agreement with the preventive role of SCH 23390 against the development of behavioral sensitization, H a m a m u r a et al. 14 demonstrated, using in vivo microdialysis, that the degree to which dopamine in striatal perfusates increased following MAP challenge was significantly greater in rats treated with repeated MAP than in those treated with repeated saline or MAP in combination with SCH 23390. Several lines of evidence indicate that the SN may play a crucial role in the expression of some kinds of behavior induced by dopamine agonists 4'13'15. In addition, AMPinduced stereotypy is abolished by nigral injection of neuroleptics 16. Furthermore, multiple local injections of AMP into the SNc, which may induce dopamine release in the SNr from the terminals of dendrites derived from the SNc 8"25, facilitate the development of sensitization by systemically administered AMP 18. In contrast, behavioral sensitization by AMP was reported to be attenuated by concomitant microinjections of SCH 23390 into the S N r 36. These results indicate that stimulation of nigral D1 receptors by AMP or MAP, probably via excessively released dopamine from dendrites, is necessary for the development of behavioral sensitization. D 1 dopamine receptors in the SNr are mostly located on the axonal terminals of striatonigral projections 3"32. The axonal terminals corresponding to D x receptors in the lateral part of the SNr originate from the neurons in the caudal part of the striatum z. The striatonigral neurons with such a topographic projection contain G A B A 28, substance p22,23, o r dynorphin B 23"42 as a neurotransmitter. Thus increased D1 receptors located on the axonal terminals of these striatonigral pathways may modulate their release of neurotransmitters. Since G A B A - and substance P-containing striatonigral pathways exert negative and positive long-loop feedback on nigrostriatal dopamine neurons, respectivelyl°'ll'17, increased nigral DI receptors may influence,the function of GABAergic or substance P-ergic long-loop feedback, resulting in dysfunction of the nigrostriatai dopaminergic system, which is one of the mechanisms of pathogenesis presumed to underlie the behavioral sensitization. In fact,
162 we and others have previously reported that chronic M A P or A M P administration altered the concentration of substance P and the n u m b e r s of its receptors in striatonigral projections 2729w. Alternatively, D1 and D 2 agonists mostly exert synergistic effects on each other in behaviors such as locomotion, rearing and sniffing when systemically administered 6'7'35. Electrophysiological studies have demonstrated such synergism in the case of microapplication of D~ a n d D 2 agonists into the SNr 43"44. Furthermore, up-regulation of Dl receptors after chronic SCH 23390 treatment enhances apomorphine-induced stereotypy 41. These findings indicate that increased D t receptors in the SNr may lead to behavioral supersensitivity to M A P in sensitized rats via synergism between the functions of DI and D 2 receptors. In the striatum and medial prefrontal cortex, neither the K o nor Bmax of [3H]SCH 23390 binding changed after any period of abstinence after subchronic M A P administration. This result for the former region agrees with the findings of Barnett et al. 5. They reported that striatal [3H]cis-flupenthixol binding in the presence of spiperone, which is considered to label D~ receptors, was unchanged REFERENCES 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 Alter, C.A. and Hauser, K., Topography of substantia nigra innervation by D1 receptor-containing striatal neurons, Brain Research, 410 (1987) 1-11. 3 Alter, C.A. and Marien, M.R., Picomolar affinity of 1251-SCH 23982 for D1 receptors in brain demonstrated with digital subtraction autoradiography, J. Neurosci., 7 (1987) 213-222. 4 Andrews, C.D. and Woodruff, G.N., Turning behavior following nigral injections of dopamine agonists and glycine, Eur. J. Pharrnacol., 84 (1982) 169-175. 5 Barnett, J.V., Segal, D.S. and Kuczenski, R., Repeated amphetamine pretreated alters the responsiveness of striatal dopamine-stimulated adenylate cyclase to amphetamine-induced desensitization, J. Pharmacol. Exp. Ther., 242 (1987) 40-47. 6 Braun, A.R. and Chase, T.N., Obligatory DI/D 2 receptor interaction in the generation of dopamine agonist related behaviors, Eur. J. Pharmacol., 131 (1986) 301-306. 7 Carson, J.H., Bergstrom, D.A. and Waiters, J.R., Stimulation of both DI and D2 dopamine receptors necessary for full expression of postsynaptic effects of dopamine agonists: a neurophysiological study, Brain Research, 400 (1987) 205-218. 8 Cheramy, A., Leviel, V. and Glowinsky, J., Dendritic release of dopamine in the substantia nigra, Nature, 289 (1981) 537-542. 9 Christensen, A.V., Arnt, J., Hyttel, J., Larsen, J.-J. and Svendsen, O., Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics, Life Sci., 34 (1984) 1529-1540. 10 Davis, J. and Dray, A., Substance P in the substantia nigra, Brain Research, 107 (1976) 623-627. 11 Dray, A., The striatum and substantia nigra: a commentary on their relationship, Neuroscience, 4 (1979) 1407-1439.
after acute and repeated A M P administration. However, there was a transient decrease in K~ in the mesolimbic area 24 h after the last injection of MAP. The K d in the mesolimbic area then recovered within 7 days after the last injection. Therefore it is unlikely that this change in the mesolimbic area forms the biological basis underlying M A P - i n d u c e d behavioral sensitization, which lasts for a long period, and instead it may be concerned with a change secondary to excessive release of dopamine by MAP, or a withdrawal p h e n o m e n o n from subchronic MAP. In conclusion, we have demonstrated for the first time a lasting increase in D 1 d o p a m i n e receptors of the SNr after subchronic M A P administration. We speculated that increased nigral D 1 receptors may be associated with M A P - i n d u c e d behavioral sensitization, probably via either induction of functional changes in the striatonigral long-loop feedback to nigrostriatal dopamine neurons, or synergism in the SNr between D 1 and D 2 receptors. Acknowledgements. This work was supported in part by a Research Grant for the Biological Study of Schizophrenia from the Japanese Ministry of Health and Welfare. The authors wish to thank Schering Co. for the gift of SCH 23390. 12 Ellinwood, E.H., Sudilovski, A. and Nelson, L.J., Evolving behavior in the clinical and experimental amphetamine (model) psychosis, Am. J. Psychiatry, 130 (1973) 1088-1093. 13 Fletcher, G.H. and Start, M.S., Role of substantia nigra in the expression of dopamine DI receptor-mediated and D2 receptormediated behaviors, Neuroscience, 23 (1987) 1001-/010. 14 Hamamura, rE, Akimoto, K., Kashihara, K., Okumura, K., Ujike, H., Akiyama, K. and Otsuki, S., Co-administration of either selective D-1 and D-2 dopamine antagonists with methamphetamine prevent methamphetamine-induced behavioral sensitization and neurochemical change, studied by in vivo intracerebral dialysis, Brain Research, in press. 15 Iorio, L.C., Barnett, A., Leitz, F.H:, Houser, V.P. and Korduba, C.A., SCH 23390, a potential benzazepine antipsychotic with unique interaction on dopaminergic systems, J. Pharmacol. Exp. Ther., 266 (1983) 462-468. 16 Jackson, E.A. and Kelly, P.H., Role of nigral dopamine in amphetamine-induced locomotor activity, Brain Research, 278 (1983) 366-369. 17 James, T.A. and Starr, M.S., Effects of substance P injected into substantia nigra, J. Pharmacol., 65 (1979) 423-429. 18 Kalivas, P.W. and Weber, B., Amphetamine injection into ventral mesencephalon sensitizes rats to peripheral amphetamine and cocaine, J. Pharmacol. Exp. Ther., 245 (1988) 1095-1102. 19 Kashihara, K., Fujiwara, T. and Sato, M., Continuous suppression of methamphetamine-induced supersensitivity by chronic haloperidol administration, Psychiat. Neurol. Jpn., 86 (1984) 928-932 (in Japanese). 20 Kazahaya, Y., Akimoto, K. and Otsuki, S., Subchronic methamphetamine treatment enhances methamphetamine- or cocaine-induced efflux in vivo, Biol. Psychiatry, 25 (1989)903-912. 21 Klawans, H.L. and Margolin, D.I., Amphetamine-induced dopaminergic hypersensitivity in guinea pigs, Arch. Gen. Psychiatry, 32 (1975) 725-732. 22 Kohno, J., Shiosaka, S., Inagaki, S. and Tohyama, M., Two distinct strio-nigral substance P pathways in the rat: an experimental immunohistochemical study, Brain Research, 308 (1984)
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159
BRES 16283
Lasting increase in D 1 dopamine receptors in the lateral part of the substantia nigra pars reticulata after subchronic methamphetamine administration Hiroshi Ujike, Kazufumi Akiyama, Hiroshi Nishikawa, Taichi Onoue and Saburo Otsuki Department of Neuropsychiatry, Okayama University Medical School, Okayama 700 (Japan) (Accepted 21 August 1990)
Key words: Methamphetamine; D:receptor; Dopamine receptor; [3H]SCH23390; Substantia nigra pars reticulata; Behavioral sensitization
To examine the possible involvement of D 1dopamine receptors in behavioral sensitization induced by subchronic methamphetamine (MAP) administration, regional D1 receptors labeled with [3H]SCH 23390 were examined using binding assay and quantitative autoradiography. Rats received 4 mg/kg/day MAP (i.p.) for 14 days, and were decapitated after an abstinence period of 24 h, 7 days or 21 days. In MAP-treated rats, a significant decrease in Kd in the mesolimbic area was observed 24 h but not 7 days after the last injection. Neither Kd nor B~ax changed in the striatum or medial prefrontal cortex of MAP-treated rats after any period of abstinence. Autoradiography revealed a significant increase in specific [3H]SCH 22390 binding in the lateral part of the substantia nigra pars reticulata (SNr) of MAP-treated rats. Since this increase lasted up to 21 days after cessation of subchronic MAP administration, it is suggested that lasting increase in the nigral D 1receptors may be associated with the biological changes underlying MAP-induced behavioral sensitization.
INTRODUCTION Repeated administration of amphetamine (AMP) or methamphetamine (MAP) to animals produces augmentation of hyperlocomotion and stereotyped behavior 21' 24,33 Such behavioral sensitization or reverse tolerance has been widely established as an animal model for AMP or MAP psychosis and paranoid-type schizophrenia in humans 12'3°'34. Thus an analogy between behavioral sensitization in animals and the clinical features of AMP or MAP psychosis is characterized by progressive augmentation with repeated administration (chronological change) and an irreversible susceptibility to recurrence in response to re-use of these psychostimulants (lasting susceptibility). Recent neurochemical studies using in vivo intracerebral dialysis, including that of the authors, have demonstrated that dopamine release is enhanced in the striatum and nucleus accumbens when AMP or MAP is rechallenged to previously sensitized animals 2°'3~. Furthermore, this enhanced dopamine release has also been shown upon re-challenge of MAP to animals sensitized by chronic cocaine 1. These findings indicate that enhanced release of dopamine may underlie the neurochemical mechanism in both MAP-induced behavioral sensitization and cross-sensitization between MAP and cocaine.
It has been shown that MAP-induced sensitization can be blocked by co-administration of haloperidot, a D1/D 2 mixed dopamine antagonist 19. We also demonstrated that co-administration of either SCH 23390 (a selective D 1 antagonist) or YM-09151-2 (a selective D 2 antagonist 37' 38) prior to each MAP injection not only blocked the acute effect of MAP but also prevented the development of behavioral sensitization 4°. In addition, we recently showed that such treatments with selective D 1 and D 2 antagonists also prevented the neurochemical changes resulting in enhanced dopamine release from the sensitized striatum 14. This prevention by D 1 antagonist of sensitization in both behavior and striatal dopamine releasability appears to be important in light of the fact that a D 1 antagonist could be applicable as a new antipsychotic drug with an ability to suppress conditioned avoidance response and to produce catalepsy 9'15. Furthermore, these findings indicate that D1 receptor may also be involved in the therapeutic effects of neuroleptics and in the pathogenesis of psychostimulant-induced sensitization. To clarify this possibility, the present study investigated regional changes in D~ receptors labeled with [3H]SCH 23390 in the rat brain after MAP-induced sensitization using a binding assay and quantitative autoradiography.
Correspondence: H. Ujike, Dept. of Neuropsychiatry, Okayama Univ. Med. School, 2-5-1 Shikata-cho, Okayama 700, Japan. 0006-8993/91/$03.50 © 1991 Elsevier Science Publishers B.V. (Biomedical Division)
160 MATERIALS AND METHODS Male Sprague-Dawley rats weighing 200-220 g at the beginning of drug administration were used. The animals were group-housed, with free access to food and water, at constant temperature (24 °C) and humidity (65%) under a standard 12-12-h light-dark cycle (lights on at 07.00 h). The rats received intraperitoneal (i.p.) injections of either 4 mg/kg MAP or saline once daily for 14 consecutive days. We had previously confirmed that this MAP administration schedule resulted in behavioral sensitization4°. MAP-treated rats were decapitated after 3 different abstinence periods of 24 h, 7 days or 21 days (MAP-24h, MAP-7d or MAP-21d group). Saline-treated rats were decapitated after an abstinence period of 24 h or 21 days (control-1 or control-2 group). The brain was rapidly removed, and the medial prefrontal cortex, striatum and mesolimbic area consisting of the nucleus accumbens and olfactory tubercle were dissected out on ice and stored below -80 °C until [3H]SCH 23390 binding assay. The remaining midbrain including the substantia nigra was embedded in O.C.T. compound and quickly frozen in dry ice-acetone. Coronal sections of rat brain (20pm thick, level AP: -5.3 mm, according to the atlas of Paxinos and Watson z6) were prepared using a coldtom (Sakura Seiki Co. CM-41) at -20 °C and thaw-mounted on gelatin/chrome alum-coated slides. These sections were stored at -20 °C until use. Binding assay The tissue was homogenized in 100 vols. of ice-cold 50 mM Tris-HCl buffer (pH 7.4) and centrifuged at 30,000 g for 10 min. This step was repeated 3 times and the final pellet was resuspended in 50 mM Tris-HC1 buffer (pH 7.4) containing 120 mM NaCI, 5 mM KCI, 2 mM CaCI 2 and 1 mM MgCI~. Aliquots of 100/A of membrane suspension were incubated in triplicate with [3H]SCH 23390 (spec. act. 71.3 Ci/mmol, New England Nuclear) at various concentrations of 0.05-8 nM in a final volume of 1 ml at room temperature for 60 min. Non-specific binding was determined in the presence of 10 ~M unlabeled SCH 23390 (Schering Co. U.S.A.). After incubation, the contents were immediately filtrated under reduced pressure through Whatman GF/B filters which had been presoaked in 0.1% polyethylenimine for 3 h. The filters were rinsed 3 times each with 5 ml of ice-cold 50 mM Tris-HCl buffer. Specific binding, which was calculated by subtracting the non-specific binding from total binding, was usually 90% of the total binding. Protein concentration was measured using a Bio-Rad protein assay kit. A utoradiography The frozen slide-mounted sections were thawed and preincubated in 50 mM Tris-HCl buffer (pH 7.4) containing the same salts as in the binding assay buffer for 15 min at room temperature. They were then transferred to incubation buffer containing 1 nM [3H]SCH 23390, and were incubated for 60 min at room temperature. Adjacent sections were incubated with 1 nM [3H]SCH 23390 in the presence of 1 /~M unlabeled SCH 23390 to determine the nonspecific binding. The incubations were terminated by 4 × 2 min washes in ice-cold 50 mM Tris-HCl buffer, and dipped in ice-cold distilled water. The slides were rapidly dried under a cool air stream, and exposed to a sheet of tritium-sensitive Ultrafilm (L.K.B. Co.) in X-ray cassettes at 4 °C for 1 week. [3H]Microscale (Amersham Co.) was co-exposed to the film as a standard. The films were developed in Kodak D-19 developer. Autoradiographic pictures obtained were analyzed with a computer-assisted imageanalyzer (Olympus CIA-10 system) for quantification of binding density. To avoid possible bias during autoradiography, samples of MAP-treated groups and their control groups were simultaneously incubated in the same baths and were exposed to the same films. Statistical analyses were performed by a one-way ANOVA followed by two-tailed Student's t-test when comparing among control-I, MAP-24h and MAP-7d, and by Student's t-test when comparing between control-2 and MAP-21d.
RESULTS Scatchard
analysis
of
the
saturation
isotherm
of
[ 3 H ] S C H 23390 i n d i c a t e d a single p o p u l a t i o n o f b i n d i n g sites in t h e t h r e e
brain regions examined.
In M A P -
t r e a t e d rats, a s i g n i f i c a n t d e c r e a s e in K,t of a b o u t 2 0 % was o b s e r v e d in t h e m e s o l i m b i c a r e a 24 h a f t e r t h e last i n j e c t i o n ( T a b l e I, F2,19 = 3.7879, P < 0.05 b y o n e - w a y ANOVA,
a n d P < 0.05 b y S t u d e n t ' s t-test). H o w e v e r ,
t h e K d r e c o v e r e d t o t h e c o n t r o l level w i t h i n 7 days. T h e r e w a s n o c h a n g e in Bma x in t h e m e s o l i m b i c a r e a . N e i t h e r Ko n o r Bm~ × c h a n g e d in t h e s t r i a t u m o r m e d i a l p r e f r o n t a l cortex of MAP-treated
rats a f t e r a n y p e r i o d of absti-
nence. Autoradiography
of
D1
receptors
labeled
with
[ 3 H ] S C H 23390 in t h e s u b s t a n t i a n i g r a p a r s r e t i c u l a t a ( S N r ) r e v e a l e d t h a t t h e r e was a g r a d i e n t d i s t r i b u t i o n o f D 1 r e c e p t o r s w i t h a h i g h e r d e n s i t y in t h e m e d i a l p a r t o f t h e S N r t h a n in t h e l a t e r a l p a r t (Fig. 1). S u c h a g r a d i e n t d i s t r i b u t i o n o f n i g r a l D 1 r e c e p t o r s is c o n s i s t e n t w i t h t h e findings of the previous
s t u d y 3. T h e r e f o r e ,
[3H]SCH
23390 b i n d i n g was m e a s u r e d s e p a r a t e l y in t w o s u b r e g i o n s of t h e m e d i a l a n d l a t e r a l SNr. [ 3 H ] S C H 23390 b i n d i n g s i g n i f i c a n t l y i n c r e a s e d b y 2 3 % ( P < 0.05) a n d 3 5 % ( P < 0.01) in t h e l a t e r a l S N r o f M A P - t r e a t e d
r a t s 24 h a n d 7
d a y s a f t e r t h e last i n j e c t i o n , r e s p e c t i v e l y ( T a b l e II, /~,ls
TABLE I Scatchard analysis o f [3H]SCH 23390 in regional brain after subchronic methamphetamine administration Rats received either saline or 4 mg/kg of methamphetamine (MAP) for 14 consecutive days, and then, were decapitated after an abstinence period of 24 h (control-l, MAP-24h group), 7 days (MAP-7d group) or 21 days (control-2, MAP-21d group). Means ± S.D., n = 7-8. K j (nM)
B m,~ (fmot/mg protein)
Striatum Control-I MAP-24 h MAP-7d
0.358 + 0.060 0.335 + 0.036 0.379 + 0.090
3007.3 + 591.3 3092.2 + 651.7 3202.5 + 657.2
Control-2 MAP-21 d
0.443 -+-0.073 0.407 ± 0.043
4201.3 + 743.9 4192.8 -+ 693.8
0.477 ± 0.090 0.396 +0.028" 0.405 ± 0.073
1848.8 ± 140,7 2039.7 ± 71.5 I917.4 _+ 189.1
0.586 ± 0.138 0.679 -+ 0.178
1426.8 -+ 239.6 1376.8 -+ 510.0
0.888 ± (/.269 (I.72(I ± (I.218
294.1 + 37.5 309.4 ± 7(I.6
Mesolimbic area Control-I MAP-24h MAP-7d Control-2 MAP-21d Medial frontal cortex Control- 1 MAP-7d
~'P < 0.05 compared with control group.
161 DISCUSSION
Fig. 1. Autography of substantia nigra using [3H]SCH23390. Notice the higher density ot lateral nigra pars reticulata of MAP-24d and MAP-7d groups than that of control-1 group. Bar = 1 mm.
= 6.2310, P < 0.01 by one-way ANOVA, P < 0.05 and P < 0.01 by Student's t-test between control-1 and MAP-24h, and between control-1 and MAP-7d group, respectively). A similar tendency of an increase by 22% in DI binding in the lateral SNr was observed even after a 21-day abstinence period
TABLE II [~H]SCH 23390 binding in two subregions of substantia nigra pars reticulata measured by quantitative autoradiography
See the legend of Table I for the meaning of groups. Means + S.D, n = 7-8. SNr-specific binding (fmol/mg tissue) Medial
Lateral
Control-1 MAP-24h MAP-7d
303.7 + 48.8 332.7 + 37.5 332.8 + 30.0
211.3 + 50.3 261.5 + 34.3b 285.2 + 34.7a
Control-2 MAP-21d
352.2 + 23.5 379.8 + 43.2
243.2 + 30.7 297.3 + 52.1c
~P < 0.01, bp < 0.05 compared with control-1 group, and cp < 0.1 compared with control-2 group.
The present study is the first to demonstrate a significant increase in [3H]SCH 23390 binding in the lateral part of the SNr which was maintained for 21 days after cessation of MAP administration. This lasting increase in D1 receptors in the SNr is intriguing in the light of our previous reports 14'4° on the effect of D 1 antagonist on the development of behavioral sensitization and accompanying dopamine releasibility. Thus, intense stereotypy, which was otherwise induced by a MAP challenge after sensitization, was abolished in the animals that were co-administered SCH 23390 with MAP. In agreement with the preventive role of SCH 23390 against the development of behavioral sensitization, H a m a m u r a et al. 14 demonstrated, using in vivo microdialysis, that the degree to which dopamine in striatal perfusates increased following MAP challenge was significantly greater in rats treated with repeated MAP than in those treated with repeated saline or MAP in combination with SCH 23390. Several lines of evidence indicate that the SN may play a crucial role in the expression of some kinds of behavior induced by dopamine agonists 4'13'15. In addition, AMPinduced stereotypy is abolished by nigral injection of neuroleptics 16. Furthermore, multiple local injections of AMP into the SNc, which may induce dopamine release in the SNr from the terminals of dendrites derived from the SNc 8"25, facilitate the development of sensitization by systemically administered AMP 18. In contrast, behavioral sensitization by AMP was reported to be attenuated by concomitant microinjections of SCH 23390 into the S N r 36. These results indicate that stimulation of nigral D1 receptors by AMP or MAP, probably via excessively released dopamine from dendrites, is necessary for the development of behavioral sensitization. D 1 dopamine receptors in the SNr are mostly located on the axonal terminals of striatonigral projections 3"32. The axonal terminals corresponding to D x receptors in the lateral part of the SNr originate from the neurons in the caudal part of the striatum z. The striatonigral neurons with such a topographic projection contain G A B A 28, substance p22,23, o r dynorphin B 23"42 as a neurotransmitter. Thus increased D1 receptors located on the axonal terminals of these striatonigral pathways may modulate their release of neurotransmitters. Since G A B A - and substance P-containing striatonigral pathways exert negative and positive long-loop feedback on nigrostriatal dopamine neurons, respectivelyl°'ll'17, increased nigral DI receptors may influence,the function of GABAergic or substance P-ergic long-loop feedback, resulting in dysfunction of the nigrostriatai dopaminergic system, which is one of the mechanisms of pathogenesis presumed to underlie the behavioral sensitization. In fact,
162 we and others have previously reported that chronic M A P or A M P administration altered the concentration of substance P and the n u m b e r s of its receptors in striatonigral projections 2729w. Alternatively, D1 and D 2 agonists mostly exert synergistic effects on each other in behaviors such as locomotion, rearing and sniffing when systemically administered 6'7'35. Electrophysiological studies have demonstrated such synergism in the case of microapplication of D~ a n d D 2 agonists into the SNr 43"44. Furthermore, up-regulation of Dl receptors after chronic SCH 23390 treatment enhances apomorphine-induced stereotypy 41. These findings indicate that increased D t receptors in the SNr may lead to behavioral supersensitivity to M A P in sensitized rats via synergism between the functions of DI and D 2 receptors. In the striatum and medial prefrontal cortex, neither the K o nor Bmax of [3H]SCH 23390 binding changed after any period of abstinence after subchronic M A P administration. This result for the former region agrees with the findings of Barnett et al. 5. They reported that striatal [3H]cis-flupenthixol binding in the presence of spiperone, which is considered to label D~ receptors, was unchanged REFERENCES 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 Alter, C.A. and Hauser, K., Topography of substantia nigra innervation by D1 receptor-containing striatal neurons, Brain Research, 410 (1987) 1-11. 3 Alter, C.A. and Marien, M.R., Picomolar affinity of 1251-SCH 23982 for D1 receptors in brain demonstrated with digital subtraction autoradiography, J. Neurosci., 7 (1987) 213-222. 4 Andrews, C.D. and Woodruff, G.N., Turning behavior following nigral injections of dopamine agonists and glycine, Eur. J. Pharrnacol., 84 (1982) 169-175. 5 Barnett, J.V., Segal, D.S. and Kuczenski, R., Repeated amphetamine pretreated alters the responsiveness of striatal dopamine-stimulated adenylate cyclase to amphetamine-induced desensitization, J. Pharmacol. Exp. Ther., 242 (1987) 40-47. 6 Braun, A.R. and Chase, T.N., Obligatory DI/D 2 receptor interaction in the generation of dopamine agonist related behaviors, Eur. J. Pharmacol., 131 (1986) 301-306. 7 Carson, J.H., Bergstrom, D.A. and Waiters, J.R., Stimulation of both DI and D2 dopamine receptors necessary for full expression of postsynaptic effects of dopamine agonists: a neurophysiological study, Brain Research, 400 (1987) 205-218. 8 Cheramy, A., Leviel, V. and Glowinsky, J., Dendritic release of dopamine in the substantia nigra, Nature, 289 (1981) 537-542. 9 Christensen, A.V., Arnt, J., Hyttel, J., Larsen, J.-J. and Svendsen, O., Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics, Life Sci., 34 (1984) 1529-1540. 10 Davis, J. and Dray, A., Substance P in the substantia nigra, Brain Research, 107 (1976) 623-627. 11 Dray, A., The striatum and substantia nigra: a commentary on their relationship, Neuroscience, 4 (1979) 1407-1439.
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