Vol. 289, Issue 1, 427-436, April 1999

S-16924, a Novel, Potential Antipsychotic with Marked Serotonin_1A Agonist Properties. IV. A Drug Discrimination Comparison with Clozapine

Mark J. Millan, Rudy Schreiber, Sabine Monneyron, Brigitte Denorme, Christophe Melon, Sophie Queriaux and Anne Dekeyne

Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, Croissy-sur-Seine, Paris, France

The novel benzodioxopyrrolidine (S-16924) displays a clozapine-like profile of interaction with multiple monoaminergic receptors, in addition to potent agonist activity at serotonin (5-HT)_1A receptors. S-16924 (2.5 mg/kg i.p.) and clozapine (5.0 mg/kg i.p.) generated robust discriminative stimuli (DS) and displayed full mutual generalization. The D₄ antagonists L-745,870 and S-18126, the D₁/D₅ antagonist SCH-39166, and the D₃ antagonist S-14297 showed at most partial generalization to S-16924 and clozapine. The D₂/D₃ antagonist raclopride fully generalized to S-16924, but only partially generalized to clozapine. The 5-HT_2A antagonist MDL-100,907 fully generalized to S-16924 and two further 5-HT_2A antagonists, fananserin and SR-46349, showed partial generalization. However, MDL-100,907, fananserin, and SR-46349 showed less pronounced generalization to clozapine. Similarly, the 5-HT_2C antagonists SB-200,646 and SB-206,553 more markedly generalized to S-16924 than to clozapine. The 5-HT_1A receptor agonist (±)-8-dihydroxy-2-(di-n-propylamino) tetralin generalized fully to S-16924 but not to clozapine. Full generalization was obtained to both S-16924 and clozapine for the clozapine congeners, olanzapine and quetiapine. In distinction, the benzisoxazole, risperidone, and the phenylindole, sertindole, weakly generalized to S-16924 and clozapine. However, the benzisoxazole ziprasidone, which possesses 5-HT_1A agonist properties, generalized fully to S-16924 but not to clozapine. Finally, the muscarinic antagonist scopolamine generalized fully to clozapine and partially to S-16924. In conclusion, S-16924 and clozapine display both communalities and differences in their "compound" DS; this likely reflects their respective complex patterns of interaction with multiple monoaminergic receptors. Although no specific receptor was identified as underlying the clozapine DS, 5-HT_1A agonist as well as D₂ and 5-HT_2A/2C antagonist properties contribute to the S-16924 DS.