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 fluexetine. 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.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jan 1999|
ASJC Scopus subject areas
- Molecular Medicine