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The D1 dopamine receptor antagonist SCH 23390 increases cocaine self-administration in the rat
Neuroscience Letters, 79 (1987) 315-320
315
Elsevier Scientific Publishers Ireland Ltd. NSL 04764
The D1 dopamine receptor antagonist SCH 23390 increases cocaine self-administration in the rat George F. K o o b l, H o a n g Thai Le I and Ian Creese 2 1Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, CA 92037 (U.S.A.) and 2Department of Neuroscience, University of California, San Diego, CA 92093 (U.S.A.)
(Received 12 February 1987; Revisedversion received 23 April 1987; Accepted 24 April 1987) Key words: Cocaine; SCH 23390; Spiperone; Rat; DI dopaminereceptor
Rats trained to intravenously self-administer cocaine hydrochloride on a fixed ratio-5 schedule were subjected to a series of systemic injections of the Dl dopamine receptor selectiveantagonist SCH 23390 and the D2 dopamine receptor selectiveantagonist spiperone. SCH 23390 produced a dose-dependent increase in cocaine intake at doses of 5, I0 and 20/tg/kg, but the D2 antagonist failed to reliably increase responding except at a dose of 10 gg/kg. These results suggest that the Dt antagonist may be more effective at blocking mesolimbicdopamine activity, and that selectiveDt receptor activation may be an important component of psychostimulant reward. Psychomotor stimulants have reinforcing properties in animal studies where subjects make an operant response that results in the intravenous administration o f drug [16, 24]. A unique property of stimulant and opiate self-administration is that animals maintain a relatively stable level of drug intake over time with regular interinjection intervals in each 3-h daily session [8, 12]. Past a given threshold dose level, animals respond to decreases in injection dose by increasing their self-administration behavior and by decreasing self-administration following increases in the injection dose. Pretreatment with low doses of neuroleptic drugs of diverse chemical structure dose-dependently increases cocaine self-administration [7, 8, 21, 26]. This result has led to the hypothesis that such drugs are blocking the reinforcing stimulus of cocaine. Further, this hypothesis has been extended to suggest that the pharmacological effect results from an action of the drug at specific sites in the central nervous system where such reinforcement is mediated [16]. Much work now suggests that a neuropharmacological site of action for the reinforcing properties o f cocaine is the result of enhanced dopaminergic synaptic activity at the terminals of the mesolimbic dopamine (DA) system in the nucleus accumbens [11, 18-21]. Since neuroleptic drugs are dopamine receptor antagonists and thus will block any augmentation of dopamine function produced by cocaine, these hypotheses are consistent with each other. Correspondence: G.F. Koob, Department of Basic and Clinical Research, Scripps Clinic and Research
Foundation, 10666 North Torrey Pines Road, La Jolla, CA 92037, U.S.A. 0304-3940/87/$ 03.50 O 1987 ElsevierScientific Publishers Ireland Ltd.
316 Biochemical techniques have made possible direct examination of the interactions of agonists and antagonists with DA receptors. These studies have clearly divided DA receptors into two distinct subtypes based on the interaction of dopamine agonists with the enzyme adenylate cyclase [5]. Activation of the D~ receptor subtype stimulates production of cAMP while activation of the D 2 receptor subtype either inhibits or has no effect on cAMP production [23]. Although neuroleptic drugs such as phenothiazines and thioxanthenes are potent antagonists at both D1 and D2 receptors [5], butyrophenones and related drugs, in contrast, are very potent antagonists of D2 receptors but exhibit weaker affinity for DI receptors. Previous work has shown that a wide variety of dopamine receptor antagonists increase cocaine self-administration and that their potencies correlated well with their anti-psychotic potencies in man [21]. This observation led to the initial conclusion that the behavioral effects caused by all neuroleptic drugs was the result of their blockade of D2 rather than D1 receptors. By inference, the reinforcing properties of cocaine would be hypothesized to occur by activation of D2 receptors in the mesolimbic area. However, no studies to date have explored possible differential effects resulting from selective blockade of the Di or D2 receptor subtypes since no selective Dl receptor antagonist existed. Surprisingly, SCH 23390, the first Dl dopamine receptor-selective antagonist, has been shown recently to block potently many dopaminergically mediated behaviors sensitive to neuroleptic antagonism [14]. In order to explore further the mechanism for the rewarding effects of psychomotor stimulants, the dopamine receptor antagonists SCH 23390 and spiperone, which show highly selective in vitro affinity for D1 and D2 dopamine receptor subtypes, respectively, were employed. These pharmacological profiles may allow new insights into the functional significance of the DA receptor subtypes. Six male Wistar rats weighing 200-250 g at the start of the experiments were initially trained to press a lever for food reward. Each animal was subsequently implanted with a chronic silastic jugular cannula under 50 mg/kg sodium pentobarbital anesthesia. The cannula was passed subcutaneously to a polyethylene assembly mounted on the animal's back which was connected to a modified cannula (Model C313G, Plastic Products). Animals were housed inside individual cages and maintained on a 12-h light-dark cycle with food and water freely available. Four days following surgery, each rat was allowed 3-h access every day to a metal lever mounted on the side wall of a standard operant-conditioning cage. The cages themselves were housed inside sound attenuating chambers. A lever-press resulted in an intravenous injection of 0.1 ml of cocaine hydrochloride (0.75 mg/kg/injection) dissolved in 0.9% saline and delivered over a period of 4 s. A swivel system allowed free movement of the animal in the cage. Coincident with the onset of the injection, a stimulus light was turned on for 20 s during which time the lever became inactive. Lever-presses during the period when the signal light was not lit were reinforced on a continuous reinforcement schedule. Those animals that demonstrated stable drug intake for 3 days were gradually trained on a fixed-ratio schedule (FR-5) requiring a total of 5 responses for each reinforced response. Once the animals reached a stable baseline of drug intake (a range of less than 10% of the daily intake over 4 days) the antagonist study was begun.
317
On a test day, the animals were pretreated 30 min prior to the daily session with subcutaneous injections of one o f the two dopamine receptor antagonists, SCH 23390 and spiperone. There were 4 different doses of SCH 23390 and spiperone (5, 10, 20 and 30/tg/kg), respectively: each dose was tested once for each animal. The drugs were prepared in a vehicle solution of 0.9% saline and injected in a volume of 1.0 ml/kg of body weight. At least two days of baseline self-administration separated testing days. Before testing with the drugs, the animals were pretreated with vehicle solution. The number of injections per hour were summed for each rat, and statistical analyses o f the data were computed using a two-factor repeated measure analyses of variance (ANOVA) with repeated measures on both dose and time (hours). Individual means comparisons were made using the Newman-Keul's a posteriori test except in the case o f spiperone where a paired t-test was used. The saline scores were used as the zero dose for analyzing both the SCH 23390 and spiperone effects. Of the 6 rats that began the study, 5 animals completed the 5, 10 and 20/tg/kg doses of both drugs. Three of the 5 rats first received SCH 23390 and two of the 5 rats first received spiperone. Fig. 1 shows the effect of each dopamine antagonist on the self-administration rate of cocaine. The points represent the mean hourly intake o f cocaine at various doses of each antagonist. SCH 23390 produced dose-dependent and time-dependent increases in cocaine intake (main effect o f dose: F = 17.15, d f = 3,12 P < 0.05). Spiperone, in contrast, did not significantly increase cocaine intake at these doses (dose and dose × time interaction P>0.05). However careful inspection of the data revealed that every rat at the 10/zg/kg dose o f spiperone increased cocaine self-administration (t = 3.00 d f = 4, P < 0.05, paired t-test). At 20/,g/kg of spiperone one rat showed an extinction-like pattern o f responding with no cocaine self-administration in the last 2 h. At a higher dose of 30 #g/kg SCH 23390 still continued to increase responding SCH 233B0
SPIPERONE
30
L~
20
Hours
Hours
Fig. I. Effect of the Dj dopamme receptor antagonist (SCH 23390-left side) and the D2 dopamine receptor antagonist (spiperone-right side) on cocaine self-administration. Each point represents the average hourly intake of cocaine by injection (n = 5). Doses are in pg/kg. For SCH 23390 doses of 5, l0 and 20 pg/kg significantly increased cocaine self-administration (P < 0.05 Newman-Keuls test following ANOVA). For spiperone the dose of 10 pg/kg significantly increased cocaine self-administration (P<0.05 paired t-test, overall ANOVA P > 0.05).
318
TABLE I EFFECTS OF 30/Jg/kg, s.c. OF SCH 23390 A N D SPIPERONE ON C O C A I N E S E L F - A D M I N I S T R A TION IN THE RAT Hour 1
Hour 2
Hour 3
SCH 23390 Rat 370 374 382 384 386
38 7 34 36 31
28 0 23 23 21
20 0 19 14 19
Spiperone Rat 370 374 384 386
19 1 17 36
19 0 0 0
21 0 0 0
17.4 +2.2
13.2 _+ 1.3
12.2 __+1.0
Saline mean ( n = 5 ) S.E.M.
at all time points in 4 out of 5 rats whereas spiperone caused an elimination of responding in the last 2 h in 3 out of 4 rats tested, see Table I. A number of studies have implicated dopaminergic systems in brain mechanisms of reinforcement. Electrical stimulation of areas of the brain that contain the cell bodies of the main dopaminergic systems, nigrostriatal and mesolimbic, is reinforcing [6, 22]. Several studies have suggested that the mesolimbic dopaminergic system may play a role in reward mechanisms, whereas the nigrostriatal dopaminergic system is more important in motor performance [4, 15, 21]. Thus, the increase in self-administration of cocaine following neuroleptic drug administration has been hypothesized to reflect a decrease in the dopaminergically-mediated reinforcing properties of cocaine since similar increases in drug intake are observed when the dose is decreased [8, I 1]. That low doses of SCH 23390 dose-dependently increased cocaine self-administration suggest that D1 receptors were involved in mediating the reinforcing effect of cocaine. The effective dosis of SCH 23390 were significantly below those which blocked locomotor effects or induced catalepsy [l] suggesting that these systemic injections were not producing non-specific actions. Numerous neuroleptic drugs such as flupenthixol, pimozide, haloperidol, chlorpromazine, metoclopramide, sulpiride, and thioridazine have been shown previously to increase cocaine self-administration at some dose level [8, 9, 21, 25-27]. Since metoclopramide and sulpiride are considered to be specific D2 receptor antagonists, the failure of spiperone (which is also a D2 specific ligand) to significantly increase cocaine self-administration except at one dose was surprising given that this drug can potently reverse many of the motor effects of dopamine agonists, as do the other neuroleptics [1, 3, 10, 13]. Indeed, as was seen at the highest dose level used in this study, spiperone can lead to inhibition of all responding. Since SCH 23390 did increase cocaine self-administration in a dose-dependent manner this would suggest
319 t h a t D l receptors m a y be at least as critical in mediating the reinforcing effects of cocaine as are D2 receptors. Similarily, SCH 23390 was more potent at blocking the locomotor stimulatory effects o f apomorphine challenge in nucleus accumbens dopamine-denervated rats than was spiperone [1]. O f all the neuroleptics examined to date in this paradigm, spiperone probably has both the greatest potency and specificity at D2 vs Dt receptors. Thus, at a given dose it will block more D2 than Di receptors, perhaps giving rise to a greater preponderance of motoric effects before blocking the reinforcing stimulus of cocaine. Sulpiride or metoclopramide are also specific D2 antagonists, and they have both been shown to increase cocaine self-administration [21]. However, data in the literature suggests that, although they are weak at Di receptors in vitro, they do show some activity in vivo [2]. Their relative weakness in binding at D2 receptors vs spiperone could make their overall in vivo pharmacological profile more similar to the classic mixed D1/D2 antagonists, Sulpiride, however, also has an unusual behavioral and pharmacological profile that is different from classical antipsychotic d r u g s which has led some to suggest that it blocks a dopamine receptor that is distinct from either D1 or D2 [17]. Another possible explanation of these differential effects is that SCH 23390 is more effective in blocking D1 receptors in the mesolimbic dopamine system whereas spiperone is more effective in blocking D2 receptors in the corpus striatum. While this hypothesized differential action is clearly not absolute (see ref. 1), an increased ability of spiperone to bind to such striatal sites could produce m o t o r effects that are incompatible with responding which might exaggerate this distinction. In any event the observation that a Dl receptor-selective antagonist is effective in blocking cocaine reward at doses that fail to produce m o t o r effects has significant implications for the neuropharmacology of dopamine in psychomotor stimulant actions.
This work was supported in part by N I A A A G r a n t AA06420, by a grant from the MacArthur Foundation, by M H Grants 32990 and R S D A 00316 (I.C.) and by the Scottish Rite Schizophrenia Research Program (I.C.). This is publication number 4716BCR from the Research Institute of Scripps Clinic, La Jolla, CA, U.S.A. I Amalric, M., Koob, G.F., Creese, I. and Swerdlow, N.R., 'Selective'D-1 and D-2 receptor antagonists fail to differentiallyalter supersensitive locomotor behavior in the rat, Life Sci., 39 (1986) 1985-1993. 2 Andersen, P.H. and Nielsen, E.B., The dopamine D1 receptor; biochemical and behavioral aspects. In G. Breese and I. Creese (Eds.), Neurobiology of Central D1 Receptors, Plenum, New York, 1986, pp. 73 91. 3 Arnt, J. and Hyttel, J., Differential involvement of dopamine D-I and D-2 receptors in the circling behavior induced by apomorphine, SKF 38393, pergolide and Ly 171555 in 6-hydroxydopaminelesioned rats, Eur. J. Pharmacol., 102 (1984) 349--354. 4 Creese, I. and Iversen, S.D., A role of forebrain dopamine systems in amphetamine-induced stereotyped behavior in the rat, Psychopharmacology,39 (1974) 345-347. 5 Creese,I., Sibley, D.R., Hamblin, M.W. and Left, S.E., The classificationof dopamine receptors: relation to radioligand binding, Annu. Rev. Neurosci., 6 (1983) 43-71. 6 Crow, T.J., A map of the rat mesencephalon for electrical self-stimulation,Brain Res., 36 (1972) 265273. 7 DeWit, H. and Wise, R.A., Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine and phenoxybenzamine,Can. J. Physiol., 31 (1978) 195 203.
320 8 Ettenberg, A., Pettit, H.O., Bloom, F.E. and Koob, G.F., Heroin and cocaine intravenous self-administration in rats: mediation by separate neural systems, Psychopharmacology, 78 (1982) 204-209. 9 Johanson, C.E., Kandel, D.A. and Bonese, K., The effects of perphenazine on self-administration behavior, Pharmacol. Biochem. Behav., 4 (1976) 427~433. 10 Klemm, W.R., Neuroleptic-induced catalepsy: a D-2 blockade phenomenon?, Pharmacol. Biochem. Behav., 23 (1985)911 915. 11 Koob, G.F., Separate neurochemical substrates for cocaine and heroin reinforcement. In R.M. Church, M.L. Commons, J. Stellar and A.R. Wagner (Eds.), Quantitative Analyses of Behavior: Biological Determinants of Behavior. Vol. 7, Erlbaum, Hillsdale, New Jersey, in press. 12 Koob, G.F., Pettit, H.O., Ettenberg, A. and Bloom, F.E., Effects of opiate antagonists and their quaternary derivatives on heroin self-administration in the rat, J. Pharmacol. Exp. Ther., 229 (1984) 481 486. 13 Meller, E., Kuga, S., Friedhoff, A.J. and Goldstein, M., Selective D-2 dopamine receptor agonists prevent catalepsy induced by SCH 23390, a selective D-I antagonist, Life Sci., 36 (1985) 1857-1866. 14 Molloy, A.G. and Waddington, J.L., Sniffing, rearing and locomotor responses to the D-I dopamine agonist R-SKF 38393 and to apomorphine: differential interactions with the D-I and D-2 antagonists SCH 23390 and metoclopramide, Eur. J. Pharmacol., 108 (1985) 305-308. 15 Phillips, A.G. and Fibiger, H.C., The role of dopamine in maintaining intra-crancial self-stimulation in the ventral tegmentum, nucleus accumbens, medial and sulcul prefrontal cortices, Can. J. Physiol., 32 (1978) 58~6. 16 Pickens, R., Meisch, R.A. and Thompson, T., Drug self-administration: an analysis of the reinforcing effects of drugs. In L.L. Iversen, S.D. Iversen and S.H. Snyder (Eds.), Handbook of Psychopharmacology, Vol. 12, Plenum, New York, 1978, pp. 1 37. 17 Protais, P., Vasse, M., Dubuc, I., Constentin, J., Sokoloff, P., Matres, M.P., Redouane, K., Schwartz, J.C., Bouthenet, M., Sales, N., Hamdi, P., Mann, A. and Wermuth, C.G., Dopaminergic behavioral responses and classes of binding sites distinguished by discriminant benzamide derivaties. In G. Woodruff, J. Poat and P.J. Roberts (Eds.), Dopaminergic Systems and their Regulation, MacMillan, London, 1986, pp. 131 152. 18 Roberts, D.C.S., Corcoran, M.E. and Fibiger, H.C., On the role of ascending catecholamine systems in intravenous self-administration of cocaine, Pharmacol. Biochem. Behav., 6 (1977) 615~520. 19 Roberts, D.C.S. and Koob, G.F., Disruption of cocaine self-administration following 6-hydroxydopamine lesions of the ventral tegmental area in rats, Pharmacol. Biochem. Behav., 17 (1982) 901 904. 20 Roberts, D.C.S., I~oob, G.F., Klonoff, P. and Fibiger, H.C., Extinction and recovery of cocaine selfadministration following 6-hydroxydopamine lesions of the nucleus accumbens, Pharmacol. Biochem. Behav., 12 (1980) 781 787. 21 Roberts, D.C.S. and Vickers, G., Atypical neuroleptics increase self-administration of cocaine: an evaluation of a behavioral screen for anti-psychotic activity, Psychopharmacology, 82 (1984) 135-139. 22 Routtenberg, A. and Malsbury, C., Brainstem pathways of reward, J. Comp. Physiol. Psychol., 68 (1969) 22 30. 23 Stoff, J.C. and Kebabian, J.W., Two dopamine receptors: biochemistry, physiology and pharmacology, Life Sci., 35 (1984) 2281 2296. 24 Thompson, T. and Pickens, R., Stimulant self-administration by animals: some comparisons with opiate self-administration, Fed. Proc. Fed. Am. Soc. Exp. Biol., 29 (1970) 6-1 I. 25 Wilson, M.C. and Schuster, C.R., The effects of chlorpromazine on psychomotor stimulant self-administration in the rhesus monkey, Psychopharmacologia, 26 (1972) 115-126. 26 Yokel, R.A. and Wise, R.A., Increased lever pressing for amphetamine after pimozide in rats: implications for a dopamine theory of reward, Science, 187 (1975) 547-549. 27 Yokel, R.A. and Wise, R.A., Attenuation of intravenous amphetamine reinforcement by central dopamine blockade in rats, Psychopharmacology, 48 (1976) 311 318.
315
Elsevier Scientific Publishers Ireland Ltd. NSL 04764
The D1 dopamine receptor antagonist SCH 23390 increases cocaine self-administration in the rat George F. K o o b l, H o a n g Thai Le I and Ian Creese 2 1Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, CA 92037 (U.S.A.) and 2Department of Neuroscience, University of California, San Diego, CA 92093 (U.S.A.)
(Received 12 February 1987; Revisedversion received 23 April 1987; Accepted 24 April 1987) Key words: Cocaine; SCH 23390; Spiperone; Rat; DI dopaminereceptor
Rats trained to intravenously self-administer cocaine hydrochloride on a fixed ratio-5 schedule were subjected to a series of systemic injections of the Dl dopamine receptor selectiveantagonist SCH 23390 and the D2 dopamine receptor selectiveantagonist spiperone. SCH 23390 produced a dose-dependent increase in cocaine intake at doses of 5, I0 and 20/tg/kg, but the D2 antagonist failed to reliably increase responding except at a dose of 10 gg/kg. These results suggest that the Dt antagonist may be more effective at blocking mesolimbicdopamine activity, and that selectiveDt receptor activation may be an important component of psychostimulant reward. Psychomotor stimulants have reinforcing properties in animal studies where subjects make an operant response that results in the intravenous administration o f drug [16, 24]. A unique property of stimulant and opiate self-administration is that animals maintain a relatively stable level of drug intake over time with regular interinjection intervals in each 3-h daily session [8, 12]. Past a given threshold dose level, animals respond to decreases in injection dose by increasing their self-administration behavior and by decreasing self-administration following increases in the injection dose. Pretreatment with low doses of neuroleptic drugs of diverse chemical structure dose-dependently increases cocaine self-administration [7, 8, 21, 26]. This result has led to the hypothesis that such drugs are blocking the reinforcing stimulus of cocaine. Further, this hypothesis has been extended to suggest that the pharmacological effect results from an action of the drug at specific sites in the central nervous system where such reinforcement is mediated [16]. Much work now suggests that a neuropharmacological site of action for the reinforcing properties o f cocaine is the result of enhanced dopaminergic synaptic activity at the terminals of the mesolimbic dopamine (DA) system in the nucleus accumbens [11, 18-21]. Since neuroleptic drugs are dopamine receptor antagonists and thus will block any augmentation of dopamine function produced by cocaine, these hypotheses are consistent with each other. Correspondence: G.F. Koob, Department of Basic and Clinical Research, Scripps Clinic and Research
Foundation, 10666 North Torrey Pines Road, La Jolla, CA 92037, U.S.A. 0304-3940/87/$ 03.50 O 1987 ElsevierScientific Publishers Ireland Ltd.
316 Biochemical techniques have made possible direct examination of the interactions of agonists and antagonists with DA receptors. These studies have clearly divided DA receptors into two distinct subtypes based on the interaction of dopamine agonists with the enzyme adenylate cyclase [5]. Activation of the D~ receptor subtype stimulates production of cAMP while activation of the D 2 receptor subtype either inhibits or has no effect on cAMP production [23]. Although neuroleptic drugs such as phenothiazines and thioxanthenes are potent antagonists at both D1 and D2 receptors [5], butyrophenones and related drugs, in contrast, are very potent antagonists of D2 receptors but exhibit weaker affinity for DI receptors. Previous work has shown that a wide variety of dopamine receptor antagonists increase cocaine self-administration and that their potencies correlated well with their anti-psychotic potencies in man [21]. This observation led to the initial conclusion that the behavioral effects caused by all neuroleptic drugs was the result of their blockade of D2 rather than D1 receptors. By inference, the reinforcing properties of cocaine would be hypothesized to occur by activation of D2 receptors in the mesolimbic area. However, no studies to date have explored possible differential effects resulting from selective blockade of the Di or D2 receptor subtypes since no selective Dl receptor antagonist existed. Surprisingly, SCH 23390, the first Dl dopamine receptor-selective antagonist, has been shown recently to block potently many dopaminergically mediated behaviors sensitive to neuroleptic antagonism [14]. In order to explore further the mechanism for the rewarding effects of psychomotor stimulants, the dopamine receptor antagonists SCH 23390 and spiperone, which show highly selective in vitro affinity for D1 and D2 dopamine receptor subtypes, respectively, were employed. These pharmacological profiles may allow new insights into the functional significance of the DA receptor subtypes. Six male Wistar rats weighing 200-250 g at the start of the experiments were initially trained to press a lever for food reward. Each animal was subsequently implanted with a chronic silastic jugular cannula under 50 mg/kg sodium pentobarbital anesthesia. The cannula was passed subcutaneously to a polyethylene assembly mounted on the animal's back which was connected to a modified cannula (Model C313G, Plastic Products). Animals were housed inside individual cages and maintained on a 12-h light-dark cycle with food and water freely available. Four days following surgery, each rat was allowed 3-h access every day to a metal lever mounted on the side wall of a standard operant-conditioning cage. The cages themselves were housed inside sound attenuating chambers. A lever-press resulted in an intravenous injection of 0.1 ml of cocaine hydrochloride (0.75 mg/kg/injection) dissolved in 0.9% saline and delivered over a period of 4 s. A swivel system allowed free movement of the animal in the cage. Coincident with the onset of the injection, a stimulus light was turned on for 20 s during which time the lever became inactive. Lever-presses during the period when the signal light was not lit were reinforced on a continuous reinforcement schedule. Those animals that demonstrated stable drug intake for 3 days were gradually trained on a fixed-ratio schedule (FR-5) requiring a total of 5 responses for each reinforced response. Once the animals reached a stable baseline of drug intake (a range of less than 10% of the daily intake over 4 days) the antagonist study was begun.
317
On a test day, the animals were pretreated 30 min prior to the daily session with subcutaneous injections of one o f the two dopamine receptor antagonists, SCH 23390 and spiperone. There were 4 different doses of SCH 23390 and spiperone (5, 10, 20 and 30/tg/kg), respectively: each dose was tested once for each animal. The drugs were prepared in a vehicle solution of 0.9% saline and injected in a volume of 1.0 ml/kg of body weight. At least two days of baseline self-administration separated testing days. Before testing with the drugs, the animals were pretreated with vehicle solution. The number of injections per hour were summed for each rat, and statistical analyses o f the data were computed using a two-factor repeated measure analyses of variance (ANOVA) with repeated measures on both dose and time (hours). Individual means comparisons were made using the Newman-Keul's a posteriori test except in the case o f spiperone where a paired t-test was used. The saline scores were used as the zero dose for analyzing both the SCH 23390 and spiperone effects. Of the 6 rats that began the study, 5 animals completed the 5, 10 and 20/tg/kg doses of both drugs. Three of the 5 rats first received SCH 23390 and two of the 5 rats first received spiperone. Fig. 1 shows the effect of each dopamine antagonist on the self-administration rate of cocaine. The points represent the mean hourly intake o f cocaine at various doses of each antagonist. SCH 23390 produced dose-dependent and time-dependent increases in cocaine intake (main effect o f dose: F = 17.15, d f = 3,12 P < 0.05). Spiperone, in contrast, did not significantly increase cocaine intake at these doses (dose and dose × time interaction P>0.05). However careful inspection of the data revealed that every rat at the 10/zg/kg dose o f spiperone increased cocaine self-administration (t = 3.00 d f = 4, P < 0.05, paired t-test). At 20/,g/kg of spiperone one rat showed an extinction-like pattern o f responding with no cocaine self-administration in the last 2 h. At a higher dose of 30 #g/kg SCH 23390 still continued to increase responding SCH 233B0
SPIPERONE
30
L~
20
Hours
Hours
Fig. I. Effect of the Dj dopamme receptor antagonist (SCH 23390-left side) and the D2 dopamine receptor antagonist (spiperone-right side) on cocaine self-administration. Each point represents the average hourly intake of cocaine by injection (n = 5). Doses are in pg/kg. For SCH 23390 doses of 5, l0 and 20 pg/kg significantly increased cocaine self-administration (P < 0.05 Newman-Keuls test following ANOVA). For spiperone the dose of 10 pg/kg significantly increased cocaine self-administration (P<0.05 paired t-test, overall ANOVA P > 0.05).
318
TABLE I EFFECTS OF 30/Jg/kg, s.c. OF SCH 23390 A N D SPIPERONE ON C O C A I N E S E L F - A D M I N I S T R A TION IN THE RAT Hour 1
Hour 2
Hour 3
SCH 23390 Rat 370 374 382 384 386
38 7 34 36 31
28 0 23 23 21
20 0 19 14 19
Spiperone Rat 370 374 384 386
19 1 17 36
19 0 0 0
21 0 0 0
17.4 +2.2
13.2 _+ 1.3
12.2 __+1.0
Saline mean ( n = 5 ) S.E.M.
at all time points in 4 out of 5 rats whereas spiperone caused an elimination of responding in the last 2 h in 3 out of 4 rats tested, see Table I. A number of studies have implicated dopaminergic systems in brain mechanisms of reinforcement. Electrical stimulation of areas of the brain that contain the cell bodies of the main dopaminergic systems, nigrostriatal and mesolimbic, is reinforcing [6, 22]. Several studies have suggested that the mesolimbic dopaminergic system may play a role in reward mechanisms, whereas the nigrostriatal dopaminergic system is more important in motor performance [4, 15, 21]. Thus, the increase in self-administration of cocaine following neuroleptic drug administration has been hypothesized to reflect a decrease in the dopaminergically-mediated reinforcing properties of cocaine since similar increases in drug intake are observed when the dose is decreased [8, I 1]. That low doses of SCH 23390 dose-dependently increased cocaine self-administration suggest that D1 receptors were involved in mediating the reinforcing effect of cocaine. The effective dosis of SCH 23390 were significantly below those which blocked locomotor effects or induced catalepsy [l] suggesting that these systemic injections were not producing non-specific actions. Numerous neuroleptic drugs such as flupenthixol, pimozide, haloperidol, chlorpromazine, metoclopramide, sulpiride, and thioridazine have been shown previously to increase cocaine self-administration at some dose level [8, 9, 21, 25-27]. Since metoclopramide and sulpiride are considered to be specific D2 receptor antagonists, the failure of spiperone (which is also a D2 specific ligand) to significantly increase cocaine self-administration except at one dose was surprising given that this drug can potently reverse many of the motor effects of dopamine agonists, as do the other neuroleptics [1, 3, 10, 13]. Indeed, as was seen at the highest dose level used in this study, spiperone can lead to inhibition of all responding. Since SCH 23390 did increase cocaine self-administration in a dose-dependent manner this would suggest
319 t h a t D l receptors m a y be at least as critical in mediating the reinforcing effects of cocaine as are D2 receptors. Similarily, SCH 23390 was more potent at blocking the locomotor stimulatory effects o f apomorphine challenge in nucleus accumbens dopamine-denervated rats than was spiperone [1]. O f all the neuroleptics examined to date in this paradigm, spiperone probably has both the greatest potency and specificity at D2 vs Dt receptors. Thus, at a given dose it will block more D2 than Di receptors, perhaps giving rise to a greater preponderance of motoric effects before blocking the reinforcing stimulus of cocaine. Sulpiride or metoclopramide are also specific D2 antagonists, and they have both been shown to increase cocaine self-administration [21]. However, data in the literature suggests that, although they are weak at Di receptors in vitro, they do show some activity in vivo [2]. Their relative weakness in binding at D2 receptors vs spiperone could make their overall in vivo pharmacological profile more similar to the classic mixed D1/D2 antagonists, Sulpiride, however, also has an unusual behavioral and pharmacological profile that is different from classical antipsychotic d r u g s which has led some to suggest that it blocks a dopamine receptor that is distinct from either D1 or D2 [17]. Another possible explanation of these differential effects is that SCH 23390 is more effective in blocking D1 receptors in the mesolimbic dopamine system whereas spiperone is more effective in blocking D2 receptors in the corpus striatum. While this hypothesized differential action is clearly not absolute (see ref. 1), an increased ability of spiperone to bind to such striatal sites could produce m o t o r effects that are incompatible with responding which might exaggerate this distinction. In any event the observation that a Dl receptor-selective antagonist is effective in blocking cocaine reward at doses that fail to produce m o t o r effects has significant implications for the neuropharmacology of dopamine in psychomotor stimulant actions.
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