The preferential dopamine D3 receptor antagonist S33138 inhibits cocaine reward and cocaine-triggered relapse to drug-seeking behavior in rats

We have previously reported that selective dopamine (DA) D-3 receptor antagonists are effective in a number of animal models of drug addiction, but not in intravenous drug self-ad ministration, suggesting a limited ability to modify drug reward. In the present study, we evaluated the actions of S33138, a novel partially selective D-3 receptor antagonist, in animal models relevant to drug addiction. S33138, at doses of 0.156 or 0.625 mg/kg (i.p.), attenuated cocaine-enhanced brain-stimulation reward (BSR), and the highest dose tested (2.5 mg/kg) produced a significant aversive-like rightward shift, in BSR rate-frequency reward functions. Further, 533138 produced biphasic effects on cocaine self-administration, i.e., a moderate dose (2.5 mg/kg, p.o.) increased, while a higher dose (5 mg/kg, p.o.) inhibited, cocaine self-ad ministration. The increase in cocaine self-administration likely reflects a compensatory response to a partial reduction in drug reward after S33138. In addition, S33138 (0.156-2.5 mg/kg, p.o.) also dose-dependently inhibited cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-enhanced BSR and cocaine-triggered reinstatement produced by lower effective doses (e.g., 0.156 or 0.625 mg/kg) of S33138 is unlikely due to impaired locomotion, as lower effective doses of S33138 decreased neither Y-max levels in the BSR paradigm, rotarod performance, nor locomotion. However, the higher doses (2.5 or 5 mg/kg) of S33138 also significantly inhibited sucrose self-administration and rotarod performance, suggesting non-D-3 receptor-mediated effects on non-drug reward and locomotion. These data suggest that lower doses of S33138 interacting essentially with D-3 receptors have pharmacotherapeutic potential in treatment of cocaine addiction, while higher doses occupying D-2 receptors may influence locomotion and non-drug reward. Published by Elsevier Ltd.