Estrogen desensitizes 5-HT1A receptors and reduces levels of G(z), G(i1) and G(i3) proteins in the hypothalamus

The present study investigated whether estrogen would desensitize hypothala mic serotonin(1A) (5-HT1A) receptors by examining the neuroendocrine respon se to 8-OH-DPAT, a 5-HT1A agonist. Rats were ovariectomized, allowed to rec over for 5 days, then given 2 daily injections of estradiol benzoate or veh icle (10 mu g/day, s.c.). Twenty-four hours after the second injection, rat s were challenged with a sub-maximal dose of 8-OH-DPAT (50 mu g/kg, sc) or saline 15 min prior to sacrifice. 8-OH-DPAT produced a significant increase in plasma oxytocin, ACTH and corticosterone levels in ovariectomized rats. While estrogen treatment for 2 days did not alter basal hormone levels, it did significantly reduce the magnitude of oxytocin, ACTH and corticosteron e responses to 8-OH-DPAT, The reduction in hormone responses was accompanie d by a significant reduction in hypothalamic levels of G(z), G(il) and G(i3 ) proteins (by 50%, 30% and 50%, respectively). These findings suggest that a reduction in these G proteins may contribute to the mechanisms underlyin g estrogen-induced desensitization of 5-HT1A receptors. The desensitization of 5-HT1A receptors has been suggested to underlie the therapeutic effects of antidepressant 5-HT uptake inhibitors (SSRIs). Thus, the present result s suggest that estrogen or estrogen-like substances in combination with SSR Is may prove effective in developing novel therapeutic strategies for neuro psychiatric disorders in women. (C) 2000 Elsevier Science Ltd. All rights r eserved.