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Cocaine-induced behaviour: dopamine D1 receptor antagonism by SCH 23390 prevents expression of conditioned sensitisation following repeated administration of cocaine
Neuropharmacology Vol. 32, No. 4, pp. 387-391, 1993 Printed in Great Britain.All rights reserved
0028-3908/93 $6.00+ 0.00 Copyright © 1993PergamonPress Ltd
COCAINE-INDUCED BEHAVIOUR: DOPAMINE Dj RECEPTOR ANTAGONISM BY SCH 23390 PREVENTS EXPRESSION OF CONDITIONED SENSITISATION FOLLOWING REPEATED ADMINISTRATION OF COCAINE A. C. MCCREARY* and C. A. MARSDENt Department of Physiology and Pharmacology, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, U.K. (Accepted 3 November 1992) Summary--Repeated administration of cocaine (15 mg/kg) (once a week for 4 weeks, day 1, 7, 14 and 21) in a conditioned environment produced significant hyperactivity and head bobbing effects which showed sensitisation. Pretreatment with the D~ antagonist SCH 23390 (0.05 mg/kg), a dose that blocked d-amphetamine (2.5 mg/kg)-induced hyperactivity, antagonised the locomotor effects of cocaine after the second (day 7), third (day 14) and fourth (day 21) administration of cocaine but not the first day (day 1). Antagonism of head bobbing occurred on all 4 (1, 7, 14 and 21) days of treatment. In contrast, haloperidol (0.1 mg/kg ) significantly reduced amphetamine-induced hyperactivity but potentiated the locomotor and stereotypic effects of cocaine, after administration of cocaine on days 1 and 7 and had no effect on cocaine-induced behaviour on days 14 and 21. The results suggest that the locomotor effects and head bobbing produced by cocaine, together with the expression of sensitisation to these effects in the conditioned environment, involve activation of post-synaptic D~ receptors. The potentiation of the effects of cocaine by a small dose of haloperidol may indicate increased release of dopamine due to blockade of pre-synaptic D2 autoreceptors. Key words--cocaine, D I receptor, D2 receptor, SCH 23390, haloperidol, cocaine-induced behaviour.
Sensitisation to the behavioural effects of cocaine in humans leads to a form of paranoid psychosis resembling schizophrenia (Angrist, 1983). Chronic administration of cocaine to rodents has been shown to induce sensitisation to the locomotor stimulatory and stereotypy inducing effects of cocaine (Tatum and Seevers, 1929; Downs and Eddy, 1932; Post and Rose, 1976; Stripling and Ellinwood, 1977; Post and Contel, 1983; Dawson, Banks, Bentley, McCreary, Dourish and Iversen, 1990), which may represent not only a model for studying paranoid psychosis associated with cocaine, but also cocaine-induced panic attacks and lethality (Jaffe, 1990). Evidence as to the neurochemical basis of cocaine-induced sensitisation is contradictory. Sensitisation has been suggested to be related to supersensitivity of post-synaptic D2 but not D~ receptor sites (Ujike, Akiyama and Otsuki, 1990). Increases in post-synaptic D2 receptors are found in the nucleus accumbens (Goeders and Kuhar, 1987; Kleven, Perry, Woolverton and Seiden, 1990; Peris, Boyson, Cass, Curella, Dwoskin, Larson, Lin, Yasuda and Zahniser, 1990). However, decreases *Present address: Pharmaceutical Sciences Institute, Aston University, Aston Triangle, Birmingham BN47ET, U.K. tTo whom correspondence should be addressed.
in D2 receptors in the striatum (Goeders and Kuhar, 1987; Kleven et al., 1990) and frontal cortex (Kleven et al., 1990) have also been demonstrated. The D1 receptor binding data with respect to treatment with cocaine is equally difficult to interpret, with no change reported in the striatum immediately after the end of treatment but decreases 2 weeks later (Kleven et al., 1990), while in the accumbens the number of D~ receptors was decreased at both time points. In contrast functional D~ receptor responsiveness (dopamine-induced inhibition of neurones in the nucleus accumbens) is enhanced by repeated administration of cocaine (Henry and White, 1991). However, Mayfield, Larson and Zahniser (1992) demonstrated no changes in D~ affinity or number in both nucleus accumbens or striatum. The aim of this study was to elucidate the role of the dopamine D~ and D 2 receptors in the expression of behavioural sensitisation to the locomotor stimulant and stereotype inducing properties of cocaine in the conditioned environment, by pharmacological intervention with D l and D2 receptor antagonists. However, drugs such as haloperidol with D2 antagonist properties reduce locomotor activity, an effect which may give the appearance that locomotor stimulation by cocaine is blocked. In preliminary experiments therefore, the effect of small doses of
387
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dopamine antagonists on amphetamine-induced hypermotility was analysed to identify suitable doses of drugs to antagonise dopamine receptors, without alteration of spontaneous activity. METHODS
Animals Fifty-four male Wistar rats (Nottingham University), weighing 190-240g at the beginning of the experiment, were used. They were housed in polythene and galvanised steel-grill cages (50 x 31 x 21 cm) in groups of 6, in temperature- and humidity-controlled rooms on a 12 hr light-dark cycle (8.00-8.00) with the light period coinciding with normal daylight hours., Water and food (Pilsburg Ltd, Birmingham, U.K.) were available ad libitum except during experimental procedures. Spontaneous locomotor activity was monitored using perspex observation cages (25 x 18 × 18 cm) placed between two photoelectric switches (Omron Tateisi Electronics, Japan). Movement of the animal from one side of the cage to the other resulted in an infra-red beam being broken and an incremental count recorded (Campden Instruments, U.K.). Head bobbing (stereotyped behaviour), which may be described as lateral movements of the head, was monitored in the observation cages described above for the full period of 2 hr according to an arbitrary rating scale of 0-3 when 0~absent, l--present 1-49% of the time, 2--present 50-99% of the time and 3--present continuously. Analysis of headbobbing was not carried out with the observer blind to treatment.
dol (0.1 mg/kg, i.p.) and cocaine (15.0mg/kg, s.c.). Each animal received one dose of its respective drug regime once per week (with a 7 day delay between treatments). No signs of necrosis or inflammation were observed around the site of injection. Rats were given vehicle, SCH 23390 or haloperidol and then placed individually into the activity monitoring cages. Forty minutes later saline or cocaine were injected and activity and head bobbing were monitored 20 min later for a period of 2 hr.
Drugs All drugs were prepared freshly each day and dissolved in the 0.9% saline vehicle and injected in a volume of 1.0ml/kg. The SCH 23390 [R(+)7 - c h i o r o - 8 - h y d r o x y - 3 - m e t h y l - 1- ohenyl- 1,2,3,4,5tetrahydro-lH-3-benzazepine hydrochloride] (RBI Chemicals) and cocaine hydrochloride (Sigma) were administered subcutaneously (s.c.) while haloperidol decanoate (Janssen, 5 mg/ml ampoules) and amphetamine sulphate were given intraperitoneally (i.p.). All doses of drugs are expressed as the salts or ester.
Statistical analyses Locomotor activity and stereotyped behaviour were analysed using a non-parametric KruskallWallis test, followed by a post-hoc two-way Mann-Whitney U-test. The effect of cocaine to induce sensitisation in the conditioned environment was analysed using a regression one-way analysis of variance, comparing day of treatment with locomotor activity. 700
Experimental protocols Experiment 1. The effect of dopamine antagonists on amphetamine-induced locomotor activity. Thirtytwo animals were assigned to 1 of 5 treatment groups (n = 6): saline and saline (1.0 ml/kg, s.c. and 1.0ml/kg, i.p.), saline (1.0ml/kg, i.p.) and amphetamine (2.5 mg/kg, i.p.); SCH 23390 (0.05 mg/kg, s.c.) and amphetamine (2.5mg/kg, i.p.); haloperidol (0.1 m g / k g , i.p.) and amphetamine (2.5 mg/kg, i.p.); haloperidol (0.5mg/kg, i.p.) and amphetamine (2.5mg/kg, i.p.). Rats were removed from home cages, given the vehicle, SCH 23390 or haloperidol and placed in locomotor activity monitors. After 1 hr, the rats were injected with amphetamine and spontaneous locomotor activity was recorded for 1 hr.
Experiment 2. The effects of dopamine antagonists on cocaine-induced locomotor activity, stereotypy and expression of sensitisation. Thirty-six animals were randomly assigned to 6 treatment groups (n = 6): saline only; saline (1.0ml/kg, s.c.) and cocaine (15.0mg/kg, s.c.); SCH 23390 (0.05mg/kg, s.c.) and saline (1.0 ml/kg, s.c.); SCH 23390 (0.05 mg/kg, s.c.) and cocaine (15.0mg/kg, s.c.); haloperidol (0.1 mg/kg, i.p.) and saline (1.0 ml/kg, s.c.); haloperi-
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Fig. 1. Effect of haloperidol and SCH 23390 on amphetamine-induced hyperactivity. Rats (n =6/group) were treated with saline, haloperidol (0.I or 0.5 mg/kg) or SCH 23390 (0.05 mg/kg) and 1 hr later given saline or amphetamine (2.5 mg/kg) and activity monitored for the following hour. Results expressed as mean crossings + SEM and analysed using Kruskall-Wallis test with post-hoc Mann-Whitney U-test. *P <0.01 compared to saline + saline; + P < 0.05 compared to saline + amphetamine; * + P < 0.01 compared to saline + amphetamine.
Cocaine and D~ receptors
389
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• Sal+Sal [ - 7 Sal+Coc Hal+Sal Hal+Coo ~ l SCH 23390+Sal SCH 23390+Coc
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Fig. 2. Effect of haloperidol and SCH 23390 on cocaine-induced hyperactivity, following administration of cocaine on day 1, 7, 14 and 21. Saline, haloperidol (0.1 mg/kg) or SCH 23390 (0.05 mg/kg) were administered 40 min before saline or cocaine (15 mg/kg) on days 1, 7, 14 and 21 and activity monitored 20 min later for the following 2 hr. Results expressed as mean crossings_ SEM and analysed using Kruskall-Wallis test with post-hoc 2-way Mann-Whitney U-test: *P < 0.05 compared to saline + saline; **P < 0.02 compared to saline + saline; ***P < 0.01 compared to saline + saline; ÷ P < 0.05 compared to saline + cocaine; §P ~<0.05 demonstrating sensitisation of the cocaine effects (ANOVA).
RESULTS
Experiment 1 Amphetamine (2.5 mg/kg, i.p.) significantly increased l o c o m o t o r activity a n d this effect was fully a n t a g o n i s e d by the D~ a n t a g o n i s t S C H 23390 ( 0 . 0 5 m g / k g , i.p.). H a l o p e r i d o l ( 0 . 1 m g / k g , i.p.) partially a n t a g o n i s e d the a m p h e t a m i n e - i n d u c e d hyperactivity a n d fully a n t a g o n i s e d at the larger dose of 0.5 m g / k g (i.p.) (Fig. 1).
Experiment 2 R a t s treated with cocaine (15 mg/kg, s.c.) o n days 1, 7, 14 a n d 21 d e m o n s t r a t e d a significant increase in l o c o m o t o r activity after each a d m i n i s t r a t i o n [P ~< 0.05, F(1,21) = 4.61] (Fig. 2). A d m i n i s t r a t i o n of cocaine also induced stereotyped b e h a v i o u r in the form of head b o b b i n g with a significantly greater response after the f o u r t h injection [day 21 P ~< 0.001, F(1,21) = 25.98], c o m p a r e d to the previous injections (Table 1). T h e Dl a n t a g o n i s t S C H 23390 (0.05 mg/kg, s.c.), given 4 0 m i n before cocaine (15 mg/kg, s.c.), significantly a n t a g o n i s e d the head b o b b i n g induced by a d m i n i s t r a t i o n o f cocaine o n days 1, 7, 14 a n d 21. S C H 23390 also m a r k e d l y reduced the cocaineinduced hyperactivity w h e n given before cocaine o n day 7, 14 a n d 21 b u t n o t day 1 (Fig. 2). S C H 23390 h a d n o stereotyped n o r l o c o m o t o r effects w h e n given
to saline-treated controls (Table 1, Fig. 1). In contrast, haloperidol (0.1 mg/kg, i.p.) did n o t a t t e n u a t e the effects o f cocaine after any of the injections o f cocaine a n d in fact p o t e n t i a t e d the cocaine-induced h y p e r l o c o m o t i o n o n days 1 a n d 7 (Fig. 2) a n d head b o b b i n g o n day 7 (Table 1). A d m i n i s t r a t i o n o f haloperidol alone to saline-treated controls h a d no significant l o c o m o t o r or stereotyped behaviour, except o n day 1 when it p r o d u c e d a small b u t significant ( P < 0.05) increase in activity. Table 1. Effects of SCH 23390 and haloperidol on head bobbing, induced by repeated administration of cocaine Day Treatment 1 7 14 21 Saline + saline 0 0 0 0 Saline + cocaine 1.0*t 1 . 1 6 * t 1 . 5 * t 1.83"? SCH 23390 saline 0 0 0 0 SCH 23390 + cocaine 0.16 0 0 0 Haloperidol + saline 0.16 0 0 0 Haloperidol + cocaine 1,66* 1.6* + 1.5* 1.6* Cocaine (15.0mg/kg) was administered on day 1, 7, 14 and 21; 40 min before the cocaine the rats were given either saline, SCH 23390 (0.05 mg/kg) or haloperidol (0.1 mg/kg) and head bobbing scored on a 0-3 scale for 20 min after administration of cocaine or saline. Results are given as the mean score with n = 6 for each group. Results were analysed using a Mann-Whitney U-test or regression ANOVA for cocaine sensitisation data. *P < 0.01 compared to saline + saline group. P < 0.01 compared to saline + cocaine group. tP ~<0.05 demonstrating sensitisation of the cocaine effects (ANOVA).
390
A.C. McCREARYand C. A. MARSDEN DISCUSSION
The main findings of the present study were firstly that repeated treatment with cocaine to rats on a weekly basis resulted in an enhanced response to the drug, in terms of both hyperiocomotion and head bobbing. Secondly, that the behavioural effects of cocaine-induced sensitisation were antagonised by the selective D~ antagonist SCH 23390 (Iorio, Barnett, Ceitz, House and Korduba, 1983; Christensen et al., 1984) but not by the relatively selective D2 compound haloperidol (Christensen et al., 1984), which in fact potentiated the behavioural effects of cocaine after the initial and second injection of cocaine; this effect being most marked with respect to hyperlocomotion. Experiment 1 was carried out to determine whether the doses of SCH 23390 (0.05mg/kg, s.c.) and haloperidol (0.1 mg/kg, i.p.), used in the subsequent study with cocaine, significantly attenuated the behavioural effects of amphetamine (2.5 mg/kg, i.p.), induced by the release of dopamine (Zetterstr6m, Sharp, Marsden and Ungerstedt, 1983; Di Chiara and Imperato, 1988). Although a greater attenuation of the response to amphetamine was obtained with the larger dose of haloperidol (0.5 mg/kg, i.p.) the smaller dose was used as it produced no sedation which could complicate the interpretation of the results with cocaine. Repeated treatment with cocaine, on a weekly basis for 4 weeks, produced a significant augmentation of the cocaine-induced hyperlocomotion and stereotypy, indicative of sensitisation to the effects of cocaine, in agreement with previous studies (Post and Rose, 1976; Dawson et al., 1990). The D~ antagonist SCH 23390 but not haloperidol not only prevented the augmentation of the conditioned response to cocaine but abolished the effects of cocaine, administered on days 7, 14 and 21; but not on locomotor activity on day 1. These results are consistent with an electrophysiological study showing that repeated administration of cocaine resulted in persistent enhancement of post-synaptic D~ receptor sensitivity in the nucleus accumbens (Henry and White, 1991) and indicate that it is the change in responsiveness of post-synaptic D~ rather than D 2 receptors that is important in the expression of sensitisation to the locomotor stimulatory properties of cocaine. However, another study has indicated that D~ receptors are also important in the expression of sensitisation to the locomotor effects of amphetamine (Stewart and Vezina, 1989). Other neurotransmitters are probably also involved; an example is the recent finding that chronic administration of cocaine also potentiates serotonergic autoreceptor mechanisms (Cunningham, Paris and Goeders, 1992). Haloperidol, in contrast to SCH 23390, increased the locomotor response produced by administration of cocaine after the first and second (day 7) injections. The effects of subsequent injection of cocaine were
not altered by haloperidol at a dose (0.1 mg/kg) shown to significantly reduce the effects of amphetamine. This result further supports the view that it is the Dj rather than the D E receptor that is important in the expression of cocaine-induced behaviour. An explanation for the augmentation of the effects of cocaine by haloperidol, after the first and second doses of the stimulant, is that haloperidol by blocking pre-synaptic somatodendritic and terminal dopamine D 2 receptors, increases the dopamine-releasing effects of cocaine by removing feed-back inhibition. Several studies have demonstrated that treatment with haloperidol increases dopaminergic neuronal firing (Bunney, Waiters, Roth and Aghajanian, 1973; Groves, Wilson, Young and Rebec, 1975), metabolism (Maidment and Marsden, 1985) and release (Di Chiara and Imperato, 1985). The failure of haloperidol to augment the effects of cocaine after the third and subsequent injections may reflect rapid development of tolerance by the dopamine D2 autoreceptor, following treatment with haloperidol (Di Chiara and Imperato, 1985) and other neuroleptics (Maidment and Marsden, 1987), with respect to the effects on the metabolism and release of dopamine. Another factor that may be involved is that repeated administration of cocaine may cause decreased sensitivity of the impulse-regulating somatodendritic autoreceptors (Kalivas and Duffy, 1988; Henry, Green and White, 1989) which, as already suggested, may contribute to the early augmentation by haloperidol. In summary, the present results indicate that D 1 receptors are important in the expression of sensitisation to the conditioned behavioural effects of cocaine, as the behavioural sensitisation was antagonised by the selective D~ compound SCH 23390. However, further experiments will be necessary to demonstrate that changes in D~ receptors are important in the development of sensitisation. In contrast, antagonism of D 2 receptors can potentiate the effects of cocaine during the early stages of repeated administration of cocaine. Acknowledgements--The authors thank Dr Susan Iversen and Merck Sharp and Dohme for financial support.
REFERENCES
Angrist B. (1983) Psychoses induced by central nervous system stimulants and related drugs. In: Stimulants: Neurochemical, Behavioural, and Clinical Perspectives
(Creese I., Ed.), pp. l 30. Raven Press, New York. Bunney B. S., Waiters J. R., Roth R.H. and Aghajanian G. K. (1973) Dopaminergic neurones: effects of antipsychotic drugs and amphetamine on single cell activity. J. Pharmac. Exp. Ther. 185: 560-571. Cunningham K. A., Paris J. M. and Goeders N. E. (1992) Chronic cocaine enhances serotonin autoregulation and serotonin uptake binding. Synapse 11:112 123. Dawson G. R., Banks R., Bentley G., McCreary A. C., Dourish C. T. and Iversen S. D. (1990) The effect of chronic administration of cocaine on locomotor activity
Cocaine and D~ receptors and on a cognitive task: evidence for differential development of tolerance and sensitisation. Br. J. Pharmac. 101: 587P. Di Chiara G. and Imperato A. (1985) Rapid tolerance to neuroleptic induced stimulation of dopamine release in freely moving rats. J. Pharmac. Exp. Ther. 235: 487--494. Di Chiara G. and Imperato A. (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the meso-limbic system of freely moving rats. Proc. Natn. Acad. Sci. U.S.A. 85: 5274-5278. Downs A. W. and Eddy N. B. (1932) The effect of repeated doses of cocaine on the rat. J. Pharmac. Exp. Ther. 46: 199 200. Goeders N. E. and Kuhar M. J. (1987) Chronic cocaine administration induces opposite changes in dopamine receptors in the striatum and nucleus accumbens. Alcohol Drug Res. 7:207 216. Groves P. M., Wilson C. J., Young S. J. and Rebec G. V. (1975) Self-inhibition by dopaminergic neurones. An alternative to the "'neuronal feedback loop" hypothesis for the mode of action of certain psychotropic drugs. Science 190: 522-529. Henry D. J. and White F. J. (1991) Repeated cocaine administration causes persistent enhancement of D~ dopamine receptor sensitivity within the rat nucleus accumbens. J. Pharmac. Exp. Ther. 258: 882-890. Henry D. J., Green M. A. and White F. J. (1989) Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: repeated administration. J. Pharmac. Exp. Ther. 251: 833-839. lorio L. C., Barnett A., Ceitz F. H., House V. P. and Korduba C. A. (1983) SCH 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems. J. Pharmac. Exp. Ther. 226: 462-468. Jaffe J. H. (1990) Drug addiction and drug abuse. In: The Pharmacological Basis of Therapeutics (Goodman Gilman L. S., Rail T. W., Nies A. S. and Taylor P., Eds), 8th edn, pp. 522 573. Macmillan, New York. Kalivas P. W. and Duffy P. (1988) Effects of daily cocaine and morphine treatment on somatodendritic and terminal field dopamine release. J. Neurochem. 50: 1498-1504. Kleven M. S., Perry B. D., Woolverton W. L. and Seiden L. S. (1990) Differential effects of chronic cocaine on D~
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and D 2 dopamine receptors in the rat. Psychopharmacology 101: $29, 106. Maidment N. T. and Marsden C. A. (1985) In vivo voltammetric and behavioural evidence for somatodendritic autoreceptor control of mesolimbic dopamine neurones. Brain Res. 338: 317-325. Maidment N. T. and Marsden C. A. (1987) Repeated atypical neuroleptic administration: effects on central dopamine metabolism monitored by in vivo voltammetry. Eur. J. Pharmae. 136: 141-149. Mayfield R. D., Larson G. and Zahniser N. R. (1992) Cocaine-induced behavioural sensitisation and D~ receptor function in rat nucleus accumbens and striatum. Brain Res. 573: 331-335. Peris J., Boyson S. J., Cass W, A., Curella P., Dwoskin L. P., Larson G., Lin L., Yasuda R. P. and Zahniser N. R. (1990) Persistence of neurochemical changes in dopamine systems after repeated cocaine administration. J. Pharmac. Exp. Ther. 253: 38-44. Post R. M. and Contra N. R. (1983) Human and animal studies of cocaine: implications for development of behavioural pathology. In: Stimulants: Neurochemical Behavioural and Clinical Perspectives (I. Creese, Ed.), pp. 169-203. Raven Press, New York. Post R. M. and Rose H. (1976) Increasing effects of repetitive cocaine administration. Nature 260:731-732 Stewart J. and Vezina P. (1989) Microinjections of SCH23390 into the ventral tegmental area and substantia nigra pars reticulata attenuate the development of sensitisation to the locomotor activating effects of systemic amphetamine. Brain Res. 495: 401-406. Stripling J. S. and Ellinwood E. H. Jr (1977) Sensitisation to cocaine following chronic administration in the rat. Adv. Behav. Biol. 1: 327-351. Tatum A. L. and Seevers M. H. (1929) Experimental cocaine addiction. J. Pharmac. Exp. Ther. 36: 401-410. Ujike H., Akiyama K. and Otsuki S. (1990) D2 but not D1 dopamine agonists produce augmented behavioural response in rats after subchronic treatment with methamphetamine on cocaine. Psychopharmacology 102: 459-464. Zetterstr6m T., Sharp T., Marsden C. A. and Ungerstedt U. (1983) In vivo measurements of dopamine and its metabolites by intracerebral dialysis: changes after d-amphetamine. J. Neurochem. 41:1769 1173.
0028-3908/93 $6.00+ 0.00 Copyright © 1993PergamonPress Ltd
COCAINE-INDUCED BEHAVIOUR: DOPAMINE Dj RECEPTOR ANTAGONISM BY SCH 23390 PREVENTS EXPRESSION OF CONDITIONED SENSITISATION FOLLOWING REPEATED ADMINISTRATION OF COCAINE A. C. MCCREARY* and C. A. MARSDENt Department of Physiology and Pharmacology, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, U.K. (Accepted 3 November 1992) Summary--Repeated administration of cocaine (15 mg/kg) (once a week for 4 weeks, day 1, 7, 14 and 21) in a conditioned environment produced significant hyperactivity and head bobbing effects which showed sensitisation. Pretreatment with the D~ antagonist SCH 23390 (0.05 mg/kg), a dose that blocked d-amphetamine (2.5 mg/kg)-induced hyperactivity, antagonised the locomotor effects of cocaine after the second (day 7), third (day 14) and fourth (day 21) administration of cocaine but not the first day (day 1). Antagonism of head bobbing occurred on all 4 (1, 7, 14 and 21) days of treatment. In contrast, haloperidol (0.1 mg/kg ) significantly reduced amphetamine-induced hyperactivity but potentiated the locomotor and stereotypic effects of cocaine, after administration of cocaine on days 1 and 7 and had no effect on cocaine-induced behaviour on days 14 and 21. The results suggest that the locomotor effects and head bobbing produced by cocaine, together with the expression of sensitisation to these effects in the conditioned environment, involve activation of post-synaptic D~ receptors. The potentiation of the effects of cocaine by a small dose of haloperidol may indicate increased release of dopamine due to blockade of pre-synaptic D2 autoreceptors. Key words--cocaine, D I receptor, D2 receptor, SCH 23390, haloperidol, cocaine-induced behaviour.
Sensitisation to the behavioural effects of cocaine in humans leads to a form of paranoid psychosis resembling schizophrenia (Angrist, 1983). Chronic administration of cocaine to rodents has been shown to induce sensitisation to the locomotor stimulatory and stereotypy inducing effects of cocaine (Tatum and Seevers, 1929; Downs and Eddy, 1932; Post and Rose, 1976; Stripling and Ellinwood, 1977; Post and Contel, 1983; Dawson, Banks, Bentley, McCreary, Dourish and Iversen, 1990), which may represent not only a model for studying paranoid psychosis associated with cocaine, but also cocaine-induced panic attacks and lethality (Jaffe, 1990). Evidence as to the neurochemical basis of cocaine-induced sensitisation is contradictory. Sensitisation has been suggested to be related to supersensitivity of post-synaptic D2 but not D~ receptor sites (Ujike, Akiyama and Otsuki, 1990). Increases in post-synaptic D2 receptors are found in the nucleus accumbens (Goeders and Kuhar, 1987; Kleven, Perry, Woolverton and Seiden, 1990; Peris, Boyson, Cass, Curella, Dwoskin, Larson, Lin, Yasuda and Zahniser, 1990). However, decreases *Present address: Pharmaceutical Sciences Institute, Aston University, Aston Triangle, Birmingham BN47ET, U.K. tTo whom correspondence should be addressed.
in D2 receptors in the striatum (Goeders and Kuhar, 1987; Kleven et al., 1990) and frontal cortex (Kleven et al., 1990) have also been demonstrated. The D1 receptor binding data with respect to treatment with cocaine is equally difficult to interpret, with no change reported in the striatum immediately after the end of treatment but decreases 2 weeks later (Kleven et al., 1990), while in the accumbens the number of D~ receptors was decreased at both time points. In contrast functional D~ receptor responsiveness (dopamine-induced inhibition of neurones in the nucleus accumbens) is enhanced by repeated administration of cocaine (Henry and White, 1991). However, Mayfield, Larson and Zahniser (1992) demonstrated no changes in D~ affinity or number in both nucleus accumbens or striatum. The aim of this study was to elucidate the role of the dopamine D~ and D 2 receptors in the expression of behavioural sensitisation to the locomotor stimulant and stereotype inducing properties of cocaine in the conditioned environment, by pharmacological intervention with D l and D2 receptor antagonists. However, drugs such as haloperidol with D2 antagonist properties reduce locomotor activity, an effect which may give the appearance that locomotor stimulation by cocaine is blocked. In preliminary experiments therefore, the effect of small doses of
387
388
A.C. MCCREARYand C. A. MARSDEN
dopamine antagonists on amphetamine-induced hypermotility was analysed to identify suitable doses of drugs to antagonise dopamine receptors, without alteration of spontaneous activity. METHODS
Animals Fifty-four male Wistar rats (Nottingham University), weighing 190-240g at the beginning of the experiment, were used. They were housed in polythene and galvanised steel-grill cages (50 x 31 x 21 cm) in groups of 6, in temperature- and humidity-controlled rooms on a 12 hr light-dark cycle (8.00-8.00) with the light period coinciding with normal daylight hours., Water and food (Pilsburg Ltd, Birmingham, U.K.) were available ad libitum except during experimental procedures. Spontaneous locomotor activity was monitored using perspex observation cages (25 x 18 × 18 cm) placed between two photoelectric switches (Omron Tateisi Electronics, Japan). Movement of the animal from one side of the cage to the other resulted in an infra-red beam being broken and an incremental count recorded (Campden Instruments, U.K.). Head bobbing (stereotyped behaviour), which may be described as lateral movements of the head, was monitored in the observation cages described above for the full period of 2 hr according to an arbitrary rating scale of 0-3 when 0~absent, l--present 1-49% of the time, 2--present 50-99% of the time and 3--present continuously. Analysis of headbobbing was not carried out with the observer blind to treatment.
dol (0.1 mg/kg, i.p.) and cocaine (15.0mg/kg, s.c.). Each animal received one dose of its respective drug regime once per week (with a 7 day delay between treatments). No signs of necrosis or inflammation were observed around the site of injection. Rats were given vehicle, SCH 23390 or haloperidol and then placed individually into the activity monitoring cages. Forty minutes later saline or cocaine were injected and activity and head bobbing were monitored 20 min later for a period of 2 hr.
Drugs All drugs were prepared freshly each day and dissolved in the 0.9% saline vehicle and injected in a volume of 1.0ml/kg. The SCH 23390 [R(+)7 - c h i o r o - 8 - h y d r o x y - 3 - m e t h y l - 1- ohenyl- 1,2,3,4,5tetrahydro-lH-3-benzazepine hydrochloride] (RBI Chemicals) and cocaine hydrochloride (Sigma) were administered subcutaneously (s.c.) while haloperidol decanoate (Janssen, 5 mg/ml ampoules) and amphetamine sulphate were given intraperitoneally (i.p.). All doses of drugs are expressed as the salts or ester.
Statistical analyses Locomotor activity and stereotyped behaviour were analysed using a non-parametric KruskallWallis test, followed by a post-hoc two-way Mann-Whitney U-test. The effect of cocaine to induce sensitisation in the conditioned environment was analysed using a regression one-way analysis of variance, comparing day of treatment with locomotor activity. 700
Experimental protocols Experiment 1. The effect of dopamine antagonists on amphetamine-induced locomotor activity. Thirtytwo animals were assigned to 1 of 5 treatment groups (n = 6): saline and saline (1.0 ml/kg, s.c. and 1.0ml/kg, i.p.), saline (1.0ml/kg, i.p.) and amphetamine (2.5 mg/kg, i.p.); SCH 23390 (0.05 mg/kg, s.c.) and amphetamine (2.5mg/kg, i.p.); haloperidol (0.1 m g / k g , i.p.) and amphetamine (2.5 mg/kg, i.p.); haloperidol (0.5mg/kg, i.p.) and amphetamine (2.5mg/kg, i.p.). Rats were removed from home cages, given the vehicle, SCH 23390 or haloperidol and placed in locomotor activity monitors. After 1 hr, the rats were injected with amphetamine and spontaneous locomotor activity was recorded for 1 hr.
Experiment 2. The effects of dopamine antagonists on cocaine-induced locomotor activity, stereotypy and expression of sensitisation. Thirty-six animals were randomly assigned to 6 treatment groups (n = 6): saline only; saline (1.0ml/kg, s.c.) and cocaine (15.0mg/kg, s.c.); SCH 23390 (0.05mg/kg, s.c.) and saline (1.0 ml/kg, s.c.); SCH 23390 (0.05 mg/kg, s.c.) and cocaine (15.0mg/kg, s.c.); haloperidol (0.1 mg/kg, i.p.) and saline (1.0 ml/kg, s.c.); haloperi-
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Fig. 1. Effect of haloperidol and SCH 23390 on amphetamine-induced hyperactivity. Rats (n =6/group) were treated with saline, haloperidol (0.I or 0.5 mg/kg) or SCH 23390 (0.05 mg/kg) and 1 hr later given saline or amphetamine (2.5 mg/kg) and activity monitored for the following hour. Results expressed as mean crossings + SEM and analysed using Kruskall-Wallis test with post-hoc Mann-Whitney U-test. *P <0.01 compared to saline + saline; + P < 0.05 compared to saline + amphetamine; * + P < 0.01 compared to saline + amphetamine.
Cocaine and D~ receptors
389
+
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1000'
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600'
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Fig. 2. Effect of haloperidol and SCH 23390 on cocaine-induced hyperactivity, following administration of cocaine on day 1, 7, 14 and 21. Saline, haloperidol (0.1 mg/kg) or SCH 23390 (0.05 mg/kg) were administered 40 min before saline or cocaine (15 mg/kg) on days 1, 7, 14 and 21 and activity monitored 20 min later for the following 2 hr. Results expressed as mean crossings_ SEM and analysed using Kruskall-Wallis test with post-hoc 2-way Mann-Whitney U-test: *P < 0.05 compared to saline + saline; **P < 0.02 compared to saline + saline; ***P < 0.01 compared to saline + saline; ÷ P < 0.05 compared to saline + cocaine; §P ~<0.05 demonstrating sensitisation of the cocaine effects (ANOVA).
RESULTS
Experiment 1 Amphetamine (2.5 mg/kg, i.p.) significantly increased l o c o m o t o r activity a n d this effect was fully a n t a g o n i s e d by the D~ a n t a g o n i s t S C H 23390 ( 0 . 0 5 m g / k g , i.p.). H a l o p e r i d o l ( 0 . 1 m g / k g , i.p.) partially a n t a g o n i s e d the a m p h e t a m i n e - i n d u c e d hyperactivity a n d fully a n t a g o n i s e d at the larger dose of 0.5 m g / k g (i.p.) (Fig. 1).
Experiment 2 R a t s treated with cocaine (15 mg/kg, s.c.) o n days 1, 7, 14 a n d 21 d e m o n s t r a t e d a significant increase in l o c o m o t o r activity after each a d m i n i s t r a t i o n [P ~< 0.05, F(1,21) = 4.61] (Fig. 2). A d m i n i s t r a t i o n of cocaine also induced stereotyped b e h a v i o u r in the form of head b o b b i n g with a significantly greater response after the f o u r t h injection [day 21 P ~< 0.001, F(1,21) = 25.98], c o m p a r e d to the previous injections (Table 1). T h e Dl a n t a g o n i s t S C H 23390 (0.05 mg/kg, s.c.), given 4 0 m i n before cocaine (15 mg/kg, s.c.), significantly a n t a g o n i s e d the head b o b b i n g induced by a d m i n i s t r a t i o n o f cocaine o n days 1, 7, 14 a n d 21. S C H 23390 also m a r k e d l y reduced the cocaineinduced hyperactivity w h e n given before cocaine o n day 7, 14 a n d 21 b u t n o t day 1 (Fig. 2). S C H 23390 h a d n o stereotyped n o r l o c o m o t o r effects w h e n given
to saline-treated controls (Table 1, Fig. 1). In contrast, haloperidol (0.1 mg/kg, i.p.) did n o t a t t e n u a t e the effects o f cocaine after any of the injections o f cocaine a n d in fact p o t e n t i a t e d the cocaine-induced h y p e r l o c o m o t i o n o n days 1 a n d 7 (Fig. 2) a n d head b o b b i n g o n day 7 (Table 1). A d m i n i s t r a t i o n o f haloperidol alone to saline-treated controls h a d no significant l o c o m o t o r or stereotyped behaviour, except o n day 1 when it p r o d u c e d a small b u t significant ( P < 0.05) increase in activity. Table 1. Effects of SCH 23390 and haloperidol on head bobbing, induced by repeated administration of cocaine Day Treatment 1 7 14 21 Saline + saline 0 0 0 0 Saline + cocaine 1.0*t 1 . 1 6 * t 1 . 5 * t 1.83"? SCH 23390 saline 0 0 0 0 SCH 23390 + cocaine 0.16 0 0 0 Haloperidol + saline 0.16 0 0 0 Haloperidol + cocaine 1,66* 1.6* + 1.5* 1.6* Cocaine (15.0mg/kg) was administered on day 1, 7, 14 and 21; 40 min before the cocaine the rats were given either saline, SCH 23390 (0.05 mg/kg) or haloperidol (0.1 mg/kg) and head bobbing scored on a 0-3 scale for 20 min after administration of cocaine or saline. Results are given as the mean score with n = 6 for each group. Results were analysed using a Mann-Whitney U-test or regression ANOVA for cocaine sensitisation data. *P < 0.01 compared to saline + saline group. P < 0.01 compared to saline + cocaine group. tP ~<0.05 demonstrating sensitisation of the cocaine effects (ANOVA).
390
A.C. McCREARYand C. A. MARSDEN DISCUSSION
The main findings of the present study were firstly that repeated treatment with cocaine to rats on a weekly basis resulted in an enhanced response to the drug, in terms of both hyperiocomotion and head bobbing. Secondly, that the behavioural effects of cocaine-induced sensitisation were antagonised by the selective D~ antagonist SCH 23390 (Iorio, Barnett, Ceitz, House and Korduba, 1983; Christensen et al., 1984) but not by the relatively selective D2 compound haloperidol (Christensen et al., 1984), which in fact potentiated the behavioural effects of cocaine after the initial and second injection of cocaine; this effect being most marked with respect to hyperlocomotion. Experiment 1 was carried out to determine whether the doses of SCH 23390 (0.05mg/kg, s.c.) and haloperidol (0.1 mg/kg, i.p.), used in the subsequent study with cocaine, significantly attenuated the behavioural effects of amphetamine (2.5 mg/kg, i.p.), induced by the release of dopamine (Zetterstr6m, Sharp, Marsden and Ungerstedt, 1983; Di Chiara and Imperato, 1988). Although a greater attenuation of the response to amphetamine was obtained with the larger dose of haloperidol (0.5 mg/kg, i.p.) the smaller dose was used as it produced no sedation which could complicate the interpretation of the results with cocaine. Repeated treatment with cocaine, on a weekly basis for 4 weeks, produced a significant augmentation of the cocaine-induced hyperlocomotion and stereotypy, indicative of sensitisation to the effects of cocaine, in agreement with previous studies (Post and Rose, 1976; Dawson et al., 1990). The D~ antagonist SCH 23390 but not haloperidol not only prevented the augmentation of the conditioned response to cocaine but abolished the effects of cocaine, administered on days 7, 14 and 21; but not on locomotor activity on day 1. These results are consistent with an electrophysiological study showing that repeated administration of cocaine resulted in persistent enhancement of post-synaptic D~ receptor sensitivity in the nucleus accumbens (Henry and White, 1991) and indicate that it is the change in responsiveness of post-synaptic D~ rather than D 2 receptors that is important in the expression of sensitisation to the locomotor stimulatory properties of cocaine. However, another study has indicated that D~ receptors are also important in the expression of sensitisation to the locomotor effects of amphetamine (Stewart and Vezina, 1989). Other neurotransmitters are probably also involved; an example is the recent finding that chronic administration of cocaine also potentiates serotonergic autoreceptor mechanisms (Cunningham, Paris and Goeders, 1992). Haloperidol, in contrast to SCH 23390, increased the locomotor response produced by administration of cocaine after the first and second (day 7) injections. The effects of subsequent injection of cocaine were
not altered by haloperidol at a dose (0.1 mg/kg) shown to significantly reduce the effects of amphetamine. This result further supports the view that it is the Dj rather than the D E receptor that is important in the expression of cocaine-induced behaviour. An explanation for the augmentation of the effects of cocaine by haloperidol, after the first and second doses of the stimulant, is that haloperidol by blocking pre-synaptic somatodendritic and terminal dopamine D 2 receptors, increases the dopamine-releasing effects of cocaine by removing feed-back inhibition. Several studies have demonstrated that treatment with haloperidol increases dopaminergic neuronal firing (Bunney, Waiters, Roth and Aghajanian, 1973; Groves, Wilson, Young and Rebec, 1975), metabolism (Maidment and Marsden, 1985) and release (Di Chiara and Imperato, 1985). The failure of haloperidol to augment the effects of cocaine after the third and subsequent injections may reflect rapid development of tolerance by the dopamine D2 autoreceptor, following treatment with haloperidol (Di Chiara and Imperato, 1985) and other neuroleptics (Maidment and Marsden, 1987), with respect to the effects on the metabolism and release of dopamine. Another factor that may be involved is that repeated administration of cocaine may cause decreased sensitivity of the impulse-regulating somatodendritic autoreceptors (Kalivas and Duffy, 1988; Henry, Green and White, 1989) which, as already suggested, may contribute to the early augmentation by haloperidol. In summary, the present results indicate that D 1 receptors are important in the expression of sensitisation to the conditioned behavioural effects of cocaine, as the behavioural sensitisation was antagonised by the selective D~ compound SCH 23390. However, further experiments will be necessary to demonstrate that changes in D~ receptors are important in the development of sensitisation. In contrast, antagonism of D 2 receptors can potentiate the effects of cocaine during the early stages of repeated administration of cocaine. Acknowledgements--The authors thank Dr Susan Iversen and Merck Sharp and Dohme for financial support.
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