GPR30 is necessary for estradiol-induced desensitization of 5- HT1A receptor signaling in the paraventricular nucleus of the rat hypothalamus

Abstract

Estrogen therapy used in combination with selective serotonin reuptake inhibitor (SSRI) treatment improves SSRI efficacy for the treatment of mood disorders. Desensitization of serotonin 1A (5-HT1A) receptors, which takes one to two weeks to develop in animals, is necessary for SSRI therapeutic efficacy. Estradiol modifies 5-HT1A receptor signaling and induces a partial desensitization in the paraventricular nucleus (PVN) of the rat within two days, but the mechanisms underlying this effect are currently unknown. The purpose of this study was to identify the estrogen receptor necessary for estradiol-induced 5-HT1A receptor desensitization. We previously showed that estrogen receptor β is not necessary for 5-HT1A receptor desensitization and that selective activation of estrogen receptor GPR30 mimics the effects of estradiol in rat PVN. Here, we used a recombinant adenovirus containing GPR30 siRNAs to decrease GPR30 expression in the PVN. Reduction of GPR30 prevented estradiol-induced desensitization of 5-HT1A receptor as measured by hormonal responses to the selective 5-HT1A receptor agonist, (+)8-OH-DPAT. To determine the possible mechanisms underlying these effects, we investigated protein and mRNA levels of 5-HT1A receptor signaling components including 5-HT1A receptor, Gαz, and RGSz1. We found that two days of estradiol increased protein and mRNA expression of RGSz1, and decreased 5-HT1A receptor protein but increased 5-HT1A mRNA; GPR30 knockdown prevented the estradiol-induced changes in 5-HT1A receptor protein in the PVN. Taken together, these data demonstrate that GPR30 is necessary for estradiol-induced changes in the 5-HT1A receptor signaling pathway and desensitization of 5-HT1A receptor signaling.