Discriminative stimulus properties of S32504, a novel D3/D2 receptor agonist and antiparkinson agent, in rats: attenuation by the antipsychotics, aripiprazole, bifeprunox, N-desmethylclozapine, and by selective antagonists at dopamine D2 but not D3 receptors

Rationale Drug-discrimination studies have proven instructive in the characterization of psychotropic agents, a procedure applied herein to the novel antiparkinson agent, S32504. This highly selective agonist at dopamine D₃ and (less potently) D₂ receptors displays potent antiparkinson, neuroprotective and antidepressant properties (Millan et al., J Pharmacol Exp Ther 309:936–950, 2004a; Millan et al., J Pharmacol Exp Ther 309:903–920, 2004b; Millan et al., J Pharmacol Exp Ther 309:921–935, 2004c). Objectives To generate a discriminative stimulus (DS) with S32504 and undertake substitution/antagonism studies with diverse antiparkinson and antipsychotic agents. Materials and methods Using a two-lever, fixed-ratio 10 schedule, rats were trained to recognize S32504 (0.04 mg/kg, s.c.) from saline. Results S32504 displayed dose-dependent and stereospecific substitution in comparison to its less active racemic form, (±) S31411, and to its inactive (−) distomer, S32601. Apomorphine, and the selective D₃/D₂ receptor agonists, ropinirole, PD128,907, 7-OH-DPAT and CGS15855A, fully (=80%) substituted for S32504, whereas D₄ and D₁/D₅ receptor agonists were ineffective. The selective D₃ vs D₂ receptor partial agonist, BP897, did not substitute for S32504 and the selective D₃ receptor antagonists, S33084, SB277,011, GR218,231, PNU99194A and S14297, did not block its DS properties. By contrast, S32504 lever selection was blocked by the preferential D₂ vs D₃ receptor antagonists, L741,626 and S23199, and by the D₂/D₃ antagonists, raclopride and haloperidol. The D₂/D₃ receptor partial agonists and antipsychotics, aripiprazole, bifeprunox, N-desmethylclozapine and preclamol did not substitute for S32504: indeed, they dose-dependently attenuated its DS properties. Conclusion The antiparkinson agent, S32504, displays DS properties principally mediated by high-efficacy activation of D₂ receptors Antipsychotics known to act as partial agonists at D₂/D₃ receptors attenuate DS properties of S32504, actions reflecting their low efficacy at these sites.