Chronic fluoxetine induces a gradual desensitization of 5-HT_1A receptors: Reductions in hypothalamic and midbrain G_i and G_o proteins and in neuroendocrine responses to a 5-HT_1A agonist

The time course of fluoxetine-induced desensitization of hypothalamic 5-hydroxytryptamine_1A receptors was examined in rats. Daily injections of fluoxetine (10 mg/kg/day) for 0, 3, 7, 14 or 22 days gradually produced a shift to the right in the dose-response curve effects of 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) on plasma adrenal corticotropic hormone, corticosterone and oxytocin. A partial reduction was observed for the adrenal corticotropic hormone and oxytocin responses to 8-OH-DPAT (50 μg/kg s.c.) after 3 days, and a maximum reduction of all hormone responses was observed after 14 days of fluoxetine injections, when the adrenal corticotropic hormone and oxytocin responses to the 50-μg/kg dose of 8-OH-DPAT were virtually blocked. To begin to examine the mechanism of 5-hydroxytryptamine_1A receptor desensitization, we determined levels of G_i and G_o proteins in the hypothalamus, midbrain and frontal cortex by using immunoblots. The hypothalamic levels of G_i1 and G_i3 proteins were significantly reduced after 7 and 14 days of fluoxetine injections. The levels of G_o and G_i2 proteins in the midbrain were significantly decreased after 3 days and remained reduced for the duration of fluoxetine injections. Fluoxetine did not reduce the concentrations of G_i and G_o proteins in the frontal cortex at any time. The similarity in time course between fluoxetine-induced reductions in hormone responses to 8-OH-DPAT and the reduction in hypothalamic levels of G_i1 and G_i3 proteins suggests that a reduction in hypothalamic levels of G_i3 and/or G_i1 proteins plays a role in the gradual desensitization of 5-hydroxytryptamine_1A receptors induced by fluoxetine.