Circulating ovarian steroid hormones, estrogen (E) and progesterone (P), have a profound modulatory influence upon an extensive network of neuronal and astroglial cells in the brain that ensure both the release of pituitary gonadotropins which triggers ovulation and the synchronous expression of behavioral receptivity. We have recently reported that the neurotransmitter dopamine (DA) exerts influences on hypothalamic steroid receptors in the absence of E and/or P. At present, the molecular, cellular and interneuronal mechanisms underlying ligand-independent regulation of steroid receptor-dependent function in the central nervous system (CNS) are undefined. Receptors for DA are expressed in those regions of the hypothalamus linked to reproduction. Since receptors for E and P have a profound influence on hypothalamic control of gonadotropin release required for ovulation and synchronous display of reproductive behavior, it is critical to understand the molecular mechanisms by which the membrane-bound DA receptor activate hypothalamic steroid receptors and their function. The goal of this project is to characterize critical signaling molecules for ligand- dependent (P) and ligand-independent (DA) progesterone receptor (PR)- dependent reproductive behavior. Since activation of PR-dependent gene transcription and reproductive behavior by DA appears to include the powerful effects of signal transduction and phosphorylation cascades initiated from the membrane, the specific aims of this project are: 1. To determine predominant second messengers and protein kinases in rat VMN associated with the induction of reproductive behavior by DA agonist and/or P treatment. 2. To ascertain whether changes in phosphorylated state of dopamine and cAMP-regulated phosphoprotein-32 (DARPP-32) and protein phosphatase inhibitor-1 (Inh-1) are associated with the induction of reproductive behavior by DA agonist and P. 3. To ascertain whether nuclear receptor co-activator molecules mediate PR-dependent reproductive behavior. 4. To characterize PR-containing cells in the ventrolateral (VL) region of the VMN and determine the specific cellular localization of PR, D5 DA receptor, DARPP-32, Inh-1, and SRC-1. 5. To characterize downstream, molecular targets in the VMN in PR-dependent transcription. The accomplishments of these aims will allow a determination of the molecular interactions of steroid hormone receptors and neurotransmitters in the regulation of female sexual behavior.
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