Daily injections of fluoxetine induce dose-dependent desensitization of hypothalamic 5-HT1A receptors: Reductions in neuroendocrine responses to 8-OH-DPAT and in levels of G(z) and G(i) proteins

The present studies examined the dose-response relationship of fluoxetine-i nduced desensitization of hypothalamic postsynaptic 5-HT1A receptors, as me asured from the reduced neuroendocrine responses to a 5-HT1A agonist. Becau se hypothalamic G(z) proteins mediate the ACTH and oxytocin responses to 5- HT1a receptor activation, we also determined the effect of fluoxetine on th e levels of G(z) proteins in the hypothalamus. Rats were injected daily for 14 days with saline or with fluoxetine doses of 0.3, 1, 3, 5, 7.5, or 10 m g/kg/day. Fluoxetine produced a dose-dependent reduction in the oxytocin, A CTH, and corticosterone responses to the 5-HT1a agonist 8-hydroxy-2-(diprop ylamino)tetralin (8-OH-DPAT, 50 mu g/kg, s.c.). The lowest fluoxetine dose that significantly, although incompletely, reduced the neuroendocrine respo nses to 8-OH-DPAT was 5 mg/kg/day. The 10 mg/kg/day dose of fluoxetine maxi mally inhibited all neuroendocrine responses to 8-OH-DPAT. Hypothalamic lev els of G(z) protein were reduced by both the 7.5 and 10 mg/kg/day doses of fluoxetine, whereas G(i1) protein levels were reduced only after the highes t dose (10 mg/kg/day) of fluoxetine. G(i2), G(i3) and G(o) levels were not reduced by any fluoxetine dose. Cytosolic levels of G(i1) and G(z) proteins were unaltered, indicating that reductions in G(z) and G(i1) proteins are not caused by a redistribution of the proteins from the membrane into the c ytosol. The results from the present study indicate that fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptor systems is do se-dependent and may be caused in part by reductions in the hypothalamic le vels of G(z) proteins.