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.
BACKGROUND
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 D(3) and (less potently) D(2) 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).


OBJECTIVE
To generate a discriminative stimulus (DS) with S32504 and undertake substitution/antagonism studies with diverse antiparkinson and antipsychotic agents.


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 D(3)/D(2) receptor agonists, ropinirole, PD128,907, 7-OH-DPAT and CGS15855A, fully (=80%) substituted for S32504, whereas D(4) and D(1)/D(5) receptor agonists were ineffective. The selective D(3) vs D(2) receptor partial agonist, BP897, did not substitute for S32504 and the selective D(3) 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 D(2) vs D(3) receptor antagonists, L741,626 and S23199, and by the D(2)/D(3) antagonists, raclopride and haloperidol. The D(2)/D(3) receptor partial agonists and antipsychotics, aripiprazole, bifeprunox, N-desmethylclozapine and preclamol did not substitute for S32504: indeed, they dose-dependently attenuated its DS properties.


CONCLUSIONS
The antiparkinson agent, S32504, displays DS properties principally mediated by high-efficacy activation of D(2) receptors Antipsychotics known to act as partial agonists at D(2)/D(3) receptors attenuate DS properties of S32504, actions reflecting their low efficacy at these sites.
Millan
Mark J
MJ
Department of Neuropharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 Chemin de Ronde, 78290, Croissy-sur-Seine, Paris, France. mark.millan@fr.netgrs.com
Iob
Loretta
L
Péglion
Jean-Louis
JL
Dekeyne
Anne
A
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001522:Behavior, Animal / Q000187:drug effects*; D001583:Benzoxazoles / Q000494:pharmacology; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010078:Oxazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D050637:Receptors, Dopamine D3 / Q000187:drug effects
D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D001583:Benzoxazoles; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010078:Oxazines; D010879:Piperazines; D015363:Quinolones; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C478818:S 32504; C058272:norclozapine; D000068180:Aripiprazole; C509981:bifeprunox; D003024:Clozapine