We have previously reported that selective
dopamine (DA) D3 receptor antagonists are effective in a number of animal models of
drug addiction, but not in intravenous
drug self-administration, suggesting a limited ability to modify
drug reward. In the present study, we evaluated the actions ofS33138, a novel partially selective D3 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,
S33138 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-administration. 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 533138 is unlikely due to impaired locomotion, as lower effective doses of
S33138 decreased neither Ymax 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-D3 receptor-mediated effects on non-
drug reward and locomotion. These data suggest that lower doses of
S33138 interacting essentially with D3 receptors have pharmacotherapeutic potential in treatment of
cocaine addiction, while higher doses occupying D2 receptors may influence locomotion and non-
drug reward.