Effect of sustained administration of the 5-HT1A receptor agonist flesinoxan on rat 5-HT neurotransmission

A short-term treatment with flesinoxan (2.5 and 5 mg/kg/day x 2 days, s.c., delivered using osmotic minipumps) decreased significantly the spontaneous filing activity of dorsal raphe serotonin (5-HT) neurons of male Sprague-D awley rats. This firing was still decreased following 1 week of treatment w ith flesinoxan (5 mg/kg/day) but was back to normal after a treatment of 2 weeks. This recovery of firing was associated with a 3-fold shift to the ri ght of the dose-response curve of the effect of the 5-HT autoreceptor agoni st lysergic acid diethylamide on the firing activity of 5-HT neurons, indic ating a desensitization of somatodendritic 5-HT1A autoreceptors. At the pos tsynaptic level, long-term treatment with flesinoxan (5 mg/kg/day x 14 days ) did not modify the responsiveness of dorsal hippocampus CA(3) pyramidal n eurons to microiontophoretic applications of 5-HT and flesinoxan nor to end ogenous 5-HT released by the electrical stimulation of the ascending 5-HT p athway, indicating an unchanged sensitivity of postsynaptic 5-HT1A receptor s. Finally, in rats treated with flesinoxan for 2 weeks, the administration of the selective 5-HT1A receptor antagonist (N-{2-[4(2-methoxyphenyl)-1-pi perazinyl]ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide trihydroxychloride ( WAY 100635, 100 and 500 mu g/kg, i.v.) did not increase the firing activity of dorsal hippocampus CA(3) pyramidal neurons, thus failing to reveal an e nhanced tonic activation of postsynaptic 5-HT1A receptors as for other anti depressant drugs, including the 5-HT1A receptor agonist gepirone. The marke d potency and the long dissociation constant of flesinoxan for the 5-HT1A r eceptors may account for the latter discrepancy. In conclusion, as for sele ctive 5-HT re-uptake inhibitors, monoamine oxidase inhibitors and 5-HT1A re ceptor agonists, flesinoxan produced most of the adaptive changes exerted b y these antidepressant drugs on the 5-HT system. (C) 1999 Elsevier Science B.V. All rights reserved.