Modification of 5‐HT neuron properties by sustained administration of the 5‐HT1A agonist gepirone: Electrophysiological studies in the rat brain

Rats given the 5-HT1A agonist gepirone for 14 days initially showed reduced firing of serotonin neurons in the dorsal raphe, which gradually returned to normal. After 14 days, the response of these neurons to intravenous LSD was markedly reduced, while responses to 8-OH-DPAT and gepirone were unchanged. Direct application of serotonin, LSD, 8-OH-DPAT, and gepirone to the neurons showed reduced responsiveness, but not to GABA. Postsynaptic hippocampal neurons remained normally responsive to serotonin and related drugs. The findings suggest that desensitization of somatodendritic 5-HT autoreceptors, combined with normal postsynaptic receptor activation, leads to increased tonic activation of postsynaptic 5-HT1A receptors, consistent with the delayed clinical anxiolytic and antidepressant effects of gepirone.

Study at a glance

Abstract

Abstract The sustained administration of the 5‐HT 1A agonist gepirone (15 mg/kg/day, s.c.) in the rat produced an initial decrease of the firing activity of dorsal raphe 5‐HT neurons which was followed by a progressive recovery to normal after 14 days of treatment. At this point in time, the effect of intravenous lysergic acid diethylamide (LSD) on the firing activity of 5‐HT neurons was markedly reduced, whereas those of 8‐hydroxy‐2‐N, N‐propylamino‐tetralin (8‐OH‐DPAT) and of gepirone were unchanged; however, the responsiveness of 5‐HT neurons to direct microintophoretic application of 5‐HT, LSD, 8‐OH‐DPAT, and gepirone, but not of GABA, was reduced. The responsiveness of postsynaptic dorsal hippocampus pyramidal neurons to 5‐HT, 8‐OH‐DPAT, and gepirone was not altered by the 14‐day gepirone treatment. The effectiveness of the electrical stimulation of the ascending 5‐HT pathway in reducing pyramidal neuron firing activity was not significantly modified in rats treated with gepirone for 14 days. Furthermore, this treatment did not alter the function of the terminal 5‐HT autoreceptor. It is concluded that the progressive restoration of the firing activity of 5‐HT neurons, due to a desensitization of the somatodendritic 5‐HT autoreceptor, combined with the direct activation of normosensitive postsynaptic 5‐HT 1A receptor by gepirone, should result in an augmented tonic activation of postsynaptic 5‐HT 1A receptors. The progressive appearance of this phenomenon would be consistent with the time course of the clinical anxiolytic, and possibly antidepressant, effects of gepirone.