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.

The Novel Dopamine D3 Receptor Antagonist NGB 2904 Inhibits Cocaine's Rewarding Effects and Cocaine-Induced Reinstatement of Drug-Seeking Behavior in Rats

“…Thus, the present finding that blockade of D 3 receptors by NGB 2904 significantly inhibits cocaine selfadministration under PR reinforcement conditions suggests that NGB 2904 antagonizes cocaine's rewarding efficacy and therefore its incentive motivational properties. This finding is consistent with previous studies demonstrating that the selective D 3 receptor antagonist SB-277011A also inhibits cocaine-seeking behavior under PR and second-order reinforcement conditions, but not under FR reinforcement conditions (Di Ciano et al, 2003;Gilbert et al, 2003;Xi et al, 2005). …”

“…In the present study, we found that NGB 2904 had no significant effect on cocaine self-administration under FR2 reinforcement conditions, but significantly lowered the break-point for cocaine self-administration under PR reinforcement conditions. This is congruent with previous findings that the selective D 3 receptor antagonist SB-277011A inhibits cocaine self-administration under a PR reinforcement schedule, but not under a low-cost highpayoff FR reinforcement schedule (Di Ciano et al, 2003;Gilbert et al, 2003;Gál and Gyertyán, 2003;Xi et al, 2005). There are three possible explanations for the ineffectiveness of NGB 2904 on FR cocaine self-administration.…”

“…The dose of cocaine was chosen on the basis of previous findings that rats self-administering cocaine at 0.5 mg/kg/infusion display highly stable selfadministration behavior. In addition, previous studies have shown that 0.5 or 1 mg/kg/infusion cocaine lies within the range of the descending limb of the cocaine dose-response self-administration curve, where stable and reliable dosedependent effects have been observed (Weissenborn et al, 1998;Parsons et al, 1998;Xi et al, 2005). Furthermore, we chose 0.5 mg/kg rather than 1 mg/kg of cocaine in order to increase the work demand (ie lever presses) of the animals for the same amount of drug intake.…”

“…Although we limited the number of maximal drug infusions, which may have masked a compensatory response, we saw neither a significant difference in the total time spent to gain the maximal 50 infusions nor a change in cocaine self-administration rate in the presence or absence of NGB 2904 pretreatment (data not shown). Third, it is possible that FR cocaine self-administration is relatively insensitive to changes in reinforcement efficacy, as suggested by several authorities in the field (eg Roberts, 1989;Katz, 1990;Arnold and Roberts, 1997), who note that FR reinforcement measures the fact of drug reinforcement, but not the degree of reinforcing efficacy (see also Gardner, 2000;Wise and Gardner, 2004;Xi et al, 2005).…”

Contributions of Dopamine D1, D2, and D3 Receptor Subtypes to the Disruptive Effects of Cocaine on Prepulse Inhibition in Mice

“…D3R KO mice also exhibit an increase in cocaine cue-conditioned hyperactivity and cocaine cueconditioned mice had increased levels of D3R mRNA in the nucleus accumbens compared to saline controls (Le Foll et al, 2002). It should be noted, however, that the effects of agonists and antagonists having preferential affinities for D3R over D2R are not entirely consistent with the effects observed with the more specific genetic manipulations of these receptor subtypes (eg Corbin et al, 1998;Le Foll et al, 2002;Xi et al, 2005). The development of more subtypeselective D 2 -family ligands or perhaps a double KO mouse in which both D2R and D3R are deleted would help to clarify the respective roles of these DA D 2 -family receptor subtypes in modulating the effects of cocaine and other psychostimulants.…”