5-HT(1A) receptor agonist properties of the antipsychotic, nemonapride: Comparison with bromerguride and clozapine

Marie Bernadette Assié, Cristina Cosi, Wouter Koek

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Abstract

5-HT(1A) 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-HT(1A) receptor agonist properties of mixed 5-HT(1A) 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-HT(1A) receptors. The present study examined the 5-HT(1A) receptor agonist activity of nemonapride and bromerguride, in comparison with clozapine, which has partial 5-HT(1A) receptor agonist properties in vitro. Here, 5-HT(1A) receptor activation was examined in vitro, by measuring forskolin-stimulated cAMP accumulation in HeLa cells expressing human 5-HT(1A) 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-HT(1A) 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-HT(1A) 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-HT(1A) receptor agonist properties both in vitro and in vivo; conceivably, these properties may play a role in its preclinical and clinical effects.

Original languageEnglish (US)
Pages (from-to)141-147
Number of pages7
JournalEuropean Journal of Pharmacology
Volume334
Issue number2-3
DOIs
StatePublished - Sep 10 1997

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Keywords

  • 5-HT (5-hydroxytryptamine serotonin)
  • 5-HT(1A) receptor
  • Antipsychotic
  • CAMP accumulation
  • Extracellular concentration
  • HA7 cells
  • Microdialysis

ASJC Scopus subject areas

  • Pharmacology

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