Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost-variable-payoff fixed-ratio cocaine self-administration in rats

Abstract

In rats, acute administration of SB-277011A, a highly selective dopamine (DA) D(3) receptor antagonist, blocks cocaine-enhanced brain stimulation reward, cocaine-seeking behaviour and reinstatement of cocaine-seeking behaviour. Here, we investigated whether SB-277011A attenuates cocaine reinforcement as assessed by cocaine self-administration under variable-cost-variable-payoff fixed-ratio (FR) and progressive-ratio (PR) reinforcement schedules. Acute i.p. administration of SB-277011A (3-24 mg/kg) did not significantly alter cocaine (0.75 mg/kg/infusion) self-administration reinforced under FR1 (one lever press for one cocaine infusion) conditions. However, acute administration of SB-277011A (24 mg/kg, i.p.) progressively attenuated cocaine self-administration when: (a) the unit dose of self-administered cocaine was lowered from 0.75 to 0.125-0.5 mg/kg, and (b) the work demand for cocaine reinforcement was increased from FR1 to FR10. Under PR (increasing number of lever presses for each successive cocaine infusion) cocaine reinforcement, acute administration of SB-277011A (6-24 mg/kg i.p.) lowered the PR break point for cocaine self-administration in a dose-dependent manner. The reduction in the cocaine (0.25-1.0 mg/kg) dose-response break-point curve produced by 24 mg/kg SB-277011A is consistent with a reduction in cocaine's reinforcing efficacy. When substituted for cocaine, SB-277011A alone did not sustain self-administration behaviour. In contrast with the mixed DA D(2)/D(3) receptor antagonist haloperidol (1 mg/kg), SB-277011A (3, 12 or 24 mg/kg) failed to impede locomotor activity, failed to impair rearing behaviour, failed to produce catalepsy and failed to impair rotarod performance. These results show that SB-277011A significantly inhibits acute cocaine-induced reinforcement except at high cocaine doses and low work requirement for cocaine. If these results extrapolate to humans, SB-277011A or similar selective DA D(3) receptor antagonists may be useful in the treatment of cocaine addiction.

Fig. 1

Effect of systemic administration of SB-277011A on cocaine self-administration (0.75 mg/kg/infusion, n = 7) under a continuous reinforcement (FR1) schedule. SB-277011A (3–24 mg/kg, i.p.) did not alter cocaine self-administration under FR1 cocaine reinforcement conditions. One-way ANOVA for repeated measurements over the SB-277011A dose range revealed no statistically significant effect of SB-277011A on cocaine self-administration (F_4,24 = 1.87, P = 0.15). Each bar represents number of self-infusions (± SEM) of cocaine.

Fig. 2

Effect of SB-277011A on cocaine self-administration under an FR10 reinforcement schedule for unit cocaine reinforcement infusions of 0.125, 0.25 or 0.5 mg/kg/infusion. (A) Representative event records of cocaine infusions (each vertical line represents an earned 0.5 mg/kg cocaine infusion under FR10 reinforcement conditions), illustrating a typical pattern of extinction responding after systemic SB-277011A (24 mg/kg, i.p.) administration. (B) Time courses of cocaine (0.25 mg/kg/infusion) self-administration after pretreatment with either the vehicle (25% 2-hydroxypropyl-β-cyclodextrin) or 24 mg/kg SB-277011A. (C) Mean number of infusions (± SEM, n = 7) during the 3-h session after administration of the vehicle or SB-277011A (24 mg/kg, i.p.) 1 h prior to the test session. *P < 0.05, **P < 0.01, ***P < 0.001; individual group comparisons using the Tukey (a) statistic, when compared with the vehicle treatment group (see more statistical details in the Results section).

Fig. 3

Effect of SB-277011A on cocaine self-administration under PR reinforcement. (A,B) Representative records of an individual animal, illustrating the effects of SB-277011A (24 mg/kg, i.p.) on the PR break point for cocaine self-administration. Each short upward mark on the cumulative lever-press records indicates one cocaine infusion. The PR break point was defined as the last completed ratio requirement (lever-presses) for a unit dose of infused cocaine. (C) Mean cocaine dose-dependent self-administration under PR reinforcement, illustrating the cocaine-dose-orderly reduction in PR break point produced by SB-277011A (24 mg/kg, i.p., n = 6 for each cocaine dose group). *P < 0.05, ***P < 0.001, individual group comparison between vehicle and SB-277011A, using the Tukey (a) statistic. (D) Percentage change in PR break point for cocaine self-administration (0.5 mg/kg/infusion) produced by 6, 12 or 24 mg/kg SB-277011A pretreatment on test day compared to PR break point for cocaine self-administration after vehicle pretreatment on test day. *P < 0.05, ***P < 0.001, individual group comparisons using the Tukey (a) statistic, when compared to the vehicle (Veh) pretreatment group.

Fig. 4

Effect of substituting cocaine, SB-277011A or saline for cocaine in animals proficient at maintaining cocaine self-administration behaviour. (A) Time-courses of cocaine, SB-277011A or saline self-administration behaviour by 20-min intervals. Two-way ANOVA for repeated measures revealed a statistically significant difference between cocaine (0.5 mg/kg/infusion) self-administration behaviour and SB-277011A (1.25 mg/kg/infusion) self-administration behaviour, and between cocaine self-administration behaviour and saline (0.08 mL/infusion) self-administration behaviour. However, there were no significant differences between SB-277011A self-administration behaviour and saline self-administration behaviour at any time point tested. *P < 0.05, ***P < 0.001, individual group comparisons, when compared with cocaine self-administration group at each time point marked. (B) Mean numbers of drug infusions summed over the 3-h test session for cocaine (0.5 mg/kg/infusion), SB-277011A (1.25 mg/kg/infusion) or saline (0.08 mL/infusion) self-administration behaviour. Both the extinction-like pattern of responding (A) and the cumulative 3-h reduction in self-administration behaviour (B) after substitution of SB-277011A suggest that SB-277011A itself has no reinforcing effect at the test dose of 1.25 mg/kg/infusion. ***P < 0.001, individual group comparisons, when compared with cocaine self-administration group. SA, self-administration; SB, SB-277011A.

Fig. 5

Effect of haloperidol (1 mg/kg i.p.) and SB-277011A (0, 3, 12 or 24 mg/kg i.p.) on locomotor activity as assessed by behaviour in (A) an infrared activity monitoring chamber, (B) observer-rated rearing behaviour, (C) catalepsy time and (D) motor coordination performance in the rotarod test (time spent on the rotarod cylinder). Haloperidol significantly reduced locomotor activity (**P < 0.001) and rearing behaviour (**P < 0.001) compared to vehicle. Haloperidol treatment also significantly increased catalepsy time (**P < 0.001) and significantly impaired motor coordination in the rotarod test (***P < 0.0001) compared to vehicle. In contrast, SB-277011A failed to alter any of these in vivo behavioural parameters. Veh, vehicle; SB 3, SB-277011A 3 mg/kg i.p.; SB 12, SB-277011A 12 mg/kg i.p.; SB 24, SB-277011A 24 mg/kg i.p.; Hal 1, haloperidol 1 mg/kg i.p.