SYNERGY BETWEEN SSRIS AND OVARIAN HORMONES

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Women suffer from disorders associated with serotonin (5-HT) deficiency, such as premenstrual syndrome (PMS) post-partum and post-menopausal depression, anxiety and bulimia. These mood and impulse control disorders are also associated with fluctuations in ovarian hormone levels. Estrogen can be used to treat some of these disorders, but serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac ) are the most effective drugs currently available. A major problem with SSRIs is the delay (2-3 weeks) in onset of clinical improvement of depression, a time which is associated with increased danger of suicide. Treatment with either fluoxetine or estrogen decreases the sensitivity of hypothalamic 5-HT1A receptor systems. These observations suggest that desensitization of 5-HT1A receptor signalling may underlie the therapeutic effectiveness of estrogen and SSRI treatments. Ovarian hormones act predominantly via genomic mechanisms, while fluoxetine induces adaptive responses via membrane proteins. Therefore, our central hypothesis is that estrogen will act synergistically with fluoxetine via complementary mechanisms to desensitize hypothalamic 5-HT1A receptor systems. Based on this hypothesis, we predict that estrogen or estrogen + progesterone will shorten the delay in the effects of SSRIs. The proposed studies will examine the mechanisms by which estrogen: 1) inhibits 5-HT1A signal transduction systems, and 2) reduces the delay in fluoxetine-induced desensitization of hypothalamic 5-HT1A receptor signalling. The proposed studies will use neuroendocrine, biochemical and molecular approaches to study the following specific aims: Specific Aim 1 will determine the doses of estrogen and progesterone that reduce hypothalamic 5-HT1A receptor function in ovariectomized rats. Specific Aim 2 will identify the estrogen receptor subtype(s) which mediate the effect of estrogen on 5-HT1A receptor systems in the hypothalamus. Specific Aim 3 will determine if estrogen shortens the delay in fluoxetine's effects on 5-HT1A receptor signalling. Specific Aim 4 will determine if progesterone increases estrogen's effectiveness in shortening the delay in fluoxetine-induced 5-HT1A receptor sub-sensitivity. The proposed studies will provide the scientific basis for the development of improved therapeutic regimens and novel drugs that provide faster clinical improvement in women suffering from PMS, depression, bulimia and anxiety disorders.