The ovarian steroid hormones, estradiol and progesterone, regulate cellular functions in the central nervous system resulting in the alterations in physiology and behavior. As in other reproductive tissues, the neural effects of estradiol and progesterone on sexual behavior are believed to require their interaction with cognate, intracellular receptors in the hormone sensitive neurons. Steroid receptors function as ligand-regulated transcription factors which undergo conformational change upon hormone binding, permitting tight association of the hormone-receptor complexes with hormone response elements on the target genes and affect neural networks involved in the control of sexual behavior. Numerous neurotransmitters are known to be involved in the neuronal processes by which steroid hormones influence sexual behavior in female mammals. The effects of neurotransmitter dopamine on sexual behavior in female rodents has been demonstrated to occur by means of cross-talk between membrane receptors for dopamine and intracellular progesterone receptors. While the cellular and molecular mechanisms involved in the interactions underlying this regulation are not well understood, it is assumed that this may occur via the phosphorylation of progesterone receptors. In the proposed research, the signal transduction pathways mediating the cross talk will be elucidated by identifying the neuronal phosphoproteins induced/phosphorylated by steroid hormones and dopamine. The interactions between these phosphoproteins and steroid hormones, estradiol and progesterone, will be examined. It will be determined whether the phosphoproteins phosphorylate the progesterone receptor per se or modulate the coregulator proteins, thereby activating the receptor and facilitating sexual behavior. These phosphoproteins will be delineated in the steroid receptor-rich regions surrounding the hypothalamus and the adjacent pre-optic area of the rat brain the areas known to be involved in the dopamine and progesterone-facilitated sexual behavior. Finally, the transcription activation functional domains of progesterone receptor involved in the dopamine activation of the receptor or its accessory proteins will be determined.

R29MH057442

1998-04-01

2004-03-31