The long term objective of these studies is to understand how genes, hormones, and environment interact and ultimately control complex social behaviors. The human and mouse genomes have been sequenced. Human endocrine mutations are common in the clinic, and engineered and sponateous mouse mutants along with hormone receptors are available for many of the enzymes that regulate hormone sythesis. Thus, the genetic bases of major hormones and their receptors are well known. But the inverse relationship, how behavior affects gene function, is relatively unexplored. The studies proposed here will dissect gene, hormone, and behavior interactions and elucidate the mechanisms by which the steroid hormone receptor, estrogen receptor alpha affects the evolutionarily essential and conserved set of behaviors that consititute male sexual behavior. We will use central administration of dopamine to activate sexual behavior in male mice lacking a functional estrogen receptor alpha gene, and we will ask if sexual experience can compensate for exogenous dopamine. In vivo microdialysis will be conducted to determine if estrogen and/or the gaseous neurotransmitter, nitric oxide, can stimulate dopamine release in the medial preoptic area. In addition, we will ask if the estrogen receptor alpha is required for female-induced dopamine release in the brain and if this is modified by sex experience. To pinpoint which dopamine receptor is essential for this behavior we will use dopamine receptor agonists and antagonists, appropriate doamine receptor knockout mice, and the progestin receptor knockout mouse to ask if dopamine acts via the unoccupied progestin receptor to initiate sexual behavior in naive males. The innovative aspects of this program include the use of pharmacology, knockout mice, and life experiences as factors that affect gene actions. Sexual dysfunctions including premature ejaculation and erectile disorders are common in men. Our understanding of the neurobiology of these disorders is limited, and the interactions between sexual experiential factors and treatment are unknown. Several clinical treatments for erectile disorder in men incorporate the use of drugs we will use for our work; nitric oxide donors and dopamine agonists. The information we will generate may help explain why patients undergoing similar drug or hormone therapies often display wide individual variations in treatment outcomes.
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