This is a revised application for a FIRST award (R29). My long-term research goal is to establish an independent multidisciplinary research program to reveal the mechanisms whereby ovarian steroid hormones regulate female sexual behavior in rats. This behavior has long served as an excellent model system for the biological basis of steroid hormone actions in brain. Previous studies have shown that oxytocin receptors (OTRs) in the hypothalamus facilitate female sexual behavior after pretreatment with estradiol and progesterone. Estradiol appears important for enhancing the level of mRNA for this protein. In the absence of progesterone, however, these estradiol-induced receptors are not sufficient for OT to augment sexual behavior. The mechanism of progesterone's permissive effects are not known. The proposed experiments will examine the mechanisms of estradiol and progesterone regulation of OTR expression and function in the rat brain. The first specific aim is to clone OTRs from rat brain. This is expected to enable the investigators to develop the appropriate reagents (e.g., probes, antisera) for subsequent studies. The second specific aim is to test the hypothesis that estradiol and progesterone regulate OTR transcripts by modulating the rate of transcription. This study will not only determine the mechanism for estradiol-induced increases in OTR mRNA, but will also determine whether progesterone actively co-regulates estradiol's effects on OTR transcription. The third specific aim will test the hypothesis that steroid hormone-induced changes in OTR binding activity in the hypothalamus are associated with alteration in second messenger production. For example, the hypothesis will be tested that the biological basis for progesterone-dependent facilitation of sexual behavior by OT is the augmentation of OTR signal transduction. A final inquiry will determine whether any increases in OTR signal transduction are mediated in part by steroid hormone-induced upregulation of G proteins associated with OTRs. Taken together, the proposed experiments will provide a detailed analysis of the multiple levels of regulation by steroid hormones of this neuropeptide receptor to permit plasticity of this biologically important behavior. Insights gained from these studies may be relevant to other examples of steroid interactions with neural circuits, such as stress responses and mood disorders.
