F15063, a potential antipsychotic with dopamine D2/D3 receptor antagonist, 5-HT1A receptor agonist and dopamine D4 receptor partial agonist properties: influence on neuronal firing and neurotransmitter release.
F15063 (N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-ethyl]-(3-cyclopenten-1-yl-benzyl)-amine) is a potential antipsychotic with dopamine D2/D3 receptor antagonist, 5-HT1A receptor agonist and dopamine D4 receptor partial agonist properties. Herein, we compared its effects on rat ventral tegmental area dopamine and dorsal raphe serotonin electrical activity with those of the dopamine D2 receptor partial agonist/5-HT1A receptor agonist, SSR181507. Further, we investigated the modulation of extracellular dopamine and noradrenaline in the medial prefrontal cortex and serotonin in the hippocampus of freely moving rats by F15063 using in vivo microdialysis. In the ventral tegmental area, F15063 (200-700 microg/kg, i.v.) did not alter the electrical activity of dopamine neurons whereas SSR181507 (250-1000 microg/kg, i.v.) partially inhibited it, consistent with dopamine D2 receptor partial agonism. Both compounds reduced the inhibition of firing rate induced by the full agonist apomorphine. In the dorsal raphe, both ligands suppressed firing activity, consistent with agonism at 5-HT1A autoreceptors, although SSR181507 (25-75 microg/kg, i.v.) was more potent than F15063 (100-300 microg/kg, i.v.). F15063 (0.63-40 mg/kg, i.p.) dose-dependently increased dopamine levels in the prefrontal cortex and decreased hippocampal 5-HT. These effects were reversed by the selective 5-HT1A receptor antagonist WAY100635 (0.16 mg/kg, s.c.), indicating that they were mediated by 5-HT1A receptors (at post- and pre-synaptic levels, respectively). In the medial prefrontal cortex, noradrenaline levels were moderately but significantly increased by F15063 at 2.5 mg/kg. In conclusion, whereas SSR181507 exhibits (partial) agonism at dopamine D2 and 5-HT1A receptors, F15063 blocks dopamine D2-like receptors whilst activating 5-HT1A receptors. Such a profile distinguishes F15063 from SSR181507 and currently available antipsychotic drugs.
Assié
Marie-Bernadette
MB
Neurobiology II Division, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81106 Castres Cedex, France. marie.bernadette.assie@pierre-fabre.com
Mnie-Filali
Ouissame
O
Ravailhe
Véronique
V
Benas
Christelle
C
Marien
Marc
M
Bétry
Cécile
C
Zimmer
Luc
L
Haddjeri
Nasser
N
Newman-Tancredi
Adrian
A