Vol. 288, Issue 1, 98-106, January 1999

Daily Injections of Fluoxetine Induce Dose-Dependent Desensitization of Hypothalamic 5-HT_1A Receptors: Reductions in Neuroendocrine Responses to 8-OH-DPAT and in Levels of G_z and G_i Proteins

D. K. Raap, S. Evans, F. Garcia, Q. Li, N. A. Muma, W. A. Wolf, G. Battaglia and L. D. Van De Kar

Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois

The present studies examined the dose-response relationship of fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT_1A receptors, as measured from the reduced neuroendocrine responses to a 5-HT_1A agonist. Because hypothalamic G_z proteins mediate the ACTH and oxytocin responses to 5-HT_1A receptor activation, we also determined the effect of fluoxetine on the 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 mg/kg/day. Fluoxetine produced a dose-dependent reduction in the oxytocin, ACTH, and corticosterone responses to the 5-HT_1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT, 50 µg/kg, s.c.). The lowest fluoxetine dose that significantly, although incompletely, reduced the neuroendocrine responses to 8-OH-DPAT was 5 mg/kg/day. The 10 mg/kg/day dose of fluoxetine maximally inhibited all neuroendocrine responses to 8-OH-DPAT. Hypothalamic levels 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 highest 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 cytosol. The results from the present study indicate that fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT_1A receptor systems is dose-dependent and may be caused in part by reductions in the hypothalamic levels of G_z proteins.