The long term objectives of the proposed studies are to provide novel approaches towards treating women who suffer from hot flashes and mood disorders during menopause. Desensitization of serotonin 1A (5-HT1A) receptor signaling both in midbrain and forebrain regions (hypothalamus, amygdala) may be an underlying mechanism for the therapeutic effects of estrogen and of Selective Serotonin Reuptake Inhibitors (SSRIs), such as fluoxetine (Prozac (r) for depression, anxiety and hot flashes in post-menopausal women. However, unlike SSRIs, which require 7-14 days to induce a therapeutic response and a desensitization of 5-HT1A receptors, estrogen can produce a desensitization of 5-HT1A receptors within 2 days of administration. This competitive renewal will investigate the mechanisms responsible for the desensitization of post-synaptic hypothalamic 5-HT1A receptor systems during treatment with estrogen. The focus of the studies is on regulatory G protein signaling-Z1 (RGSZ-1), a protein that acts as a Galphaz protein GTPase Activating Protein (Gz-GAP) that regulates the interaction between 5-HT1A receptor-coupled Galphaz proteins and effector systems (such as adenylyl cyclase or potassium channels). The overall hypothesis is that estrogen-induced desensitization of 5-HT1A receptor signaling is due to increased expression of RGSZ-1. The following aims will test this hypothesis.
Specific Aim 1 will test the hypothesis that estrogen receptor-beta (ER beta) mediates the increased expression of RGSZ-1 protein and mRNA and desensitization of the 5-HT1A receptors.
Specific Aim 2 will test the hypothesis that up-regulation of RGSZ-1 mediates the estrogen-induced desensitization of hypothalamic 5-HT1A receptors.
Specific Aim 3 will test the hypothesis that a treatment combining SSRIs (such as fluoxetine) with estrogen leads to activation of two complementary mechanisms (reduced Galphaz proteins and increased RGSZ-1 proteins, respectively), leading to a synergistic desensitization of 5-HT1A receptor signaling. The proposed studies may lead to novel targets for medications which affect the regulation of RGSZ-1 to treat women who suffer from hot flashes and mood disorders during menopause
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