Chronic fluoxetine induces a gradual desensitization of 5-HT1A receptors: Reductions in hypothalamic and midbrain G(i) and G(o) proteins and in neuroendocrine responses to a 5-HT1A agonist

  • 1 November 1996
    • journal article
    • research article
    • Vol. 279  (2) , 1035-1042
Abstract
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 mu g/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-mu g/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.