title: 5-HT1A receptor agonist properties of the antipsychotic, nemonapride: comparison with bromerguride and clozapine.
abstract: 5-HT1A receptor agonists are thought to enhance the antipsychotic-like effects of dopamine D2 receptor antagonists while reducing their potential to produce extrapyramidal side effects. Thus, 5-HT1A receptor agonist properties of mixed 5-HT1A receptor agonists/D2 receptor antagonists might be of clinical importance. The antipsychotics, clozapine and nemonapride, and the putative antipsychotic, bromerguride, have intermediate to high affinity for 5-HT1A receptors. The present study examined the 5-HT1A receptor agonist activity of nemonapride and bromerguride, in comparison with clozapine, which has partial 5-HT1A receptor agonist properties in vitro. Here, 5-HT1A receptor activation was examined in vitro, by measuring forskolin-stimulated cAMP accumulation in HeLa cells expressing human 5-HT1A receptors, and in vivo, by using microdialysis to measure the extracellular concentration of hippocampal 5-hydroxytryptamine (5-HT) in rats. Nemonapride markedly decreased both forskolin-stimulated cAMP accumulation and the extracellular concentration of 5-HT; both effects were antagonized by the 5-HT1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY100635). In contrast, clozapine only partially decreased forskolin-stimulated cAMP accumulation and extracellular 5-HT, and only its effects on cAMP accumulation were attenuated by WAY100635. Bromerguride decreased neither forskolin-stimulated cAMP accumulation nor extracellular 5-HT; instead, it antagonized the decrease of cAMP accumulation produced by 5-HT and the decrease of extracellular 5-HT produced by the 5-HT1A agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The selective D2 receptor antagonist, raclopride, affected neither forskolin-stimulated cAMP in vitro nor extracellular 5-HT in vivo. Thus, in contrast with clozapine and bromerguride, only the novel antipsychotic, nemonapride, exhibited marked 5-HT1A receptor agonist properties both in vitro and in vivo; conceivably, these properties may play a role in its preclinical and clinical effects.
authors.affiliation: Neurobiology Division II, Centre de Recherche Pierre Fabre, Castres, France.
authors.forename: M B
authors.initials: MB
authors.lastname: Assié
authors.forename: C
authors.initials: C
authors.lastname: Cosi
authors.forename: W
authors.initials: W
authors.lastname: Koek
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D006367:HeLa Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008090:Lisuride / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D001549:Benzamides; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D000242:Cyclic AMP; D008090:Lisuride; C039667:bromerguride; D003024:Clozapine; C030265:nemonapride