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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

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Abstract

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.

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  1. Department of Neuropharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 Chemin de Ronde, 78290, Croissy-sur-Seine, Paris, France

    Mark J. Millan, Loretta Iob & Anne Dekeyne

  2. Department of Chemistry B, Institut de Recherches Servier, Centre de Recherches de Suresnes, 11, Rue des Moulineaux, 92150, Suresnes, Paris, France

    Jean-Louis Péglion

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  1. Mark J. Millan
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  2. Loretta Iob
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  3. Jean-Louis Péglion
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  4. Anne Dekeyne
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Correspondence to Mark J. Millan.

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Millan, M.J., Iob, L., Péglion, JL. et al. 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. Psychopharmacology 191, 767–782 (2007). https://doi.org/10.1007/s00213-006-0567-0

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  • DOI: https://doi.org/10.1007/s00213-006-0567-0

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