F15063, a potential antipsychotic with dopamine D 2/D 3 receptor antagonist, 5-HT 1A receptor agonist and dopamine D 4 receptor partial agonist properties: Influence on neuronal firing and neurotransmitter release

Abstract

F15063 ( N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-ethyl]-(3-cyclopenten-1-yl-benzyl)-amine) is a potential antipsychotic with dopamine D 2/D 3 receptor antagonist, 5-HT 1A receptor agonist and dopamine D 4 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 D 2 receptor partial agonist/5-HT 1A 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 µg/kg, i.v.) did not alter the electrical activity of dopamine neurons whereas SSR181507 (250–1000 µg/kg, i.v.) partially inhibited it, consistent with dopamine D 2 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-HT 1A autoreceptors, although SSR181507 (25–75 µg/kg, i.v.) was more potent than F15063 (100–300 µg/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-HT 1A receptor antagonist WAY100635 (0.16 mg/kg, s.c.), indicating that they were mediated by 5-HT 1A 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 D 2 and 5-HT 1A receptors, F15063 blocks dopamine D 2-like receptors whilst activating 5-HT 1A receptors. Such a profile distinguishes F15063 from SSR181507 and currently available antipsychotic drugs.