Grant: Project Grant

Sexual arousal, desire, and pleasure are integral parts of the human condition, hardwired within our brains and bodies, yet molded by our experiences. Sexual activity is important for overall health and well-being, and numerous studies have shown the positive effects of a healthy and satisfying sex life as well as the detrimental effects of sexual dysfunctions. Distressing sexual dysfunctions occur in approximately 7 to 42% of premenopausal women for periods of time that are either lifelong or situational, of which the most common are sexual desire and orgasm disorders. Decreases in sexual arousal and desire also occur in a majority of postmenopausal women as ovarian function wanes. In the past 15 years, predictive preclinical rat models have been generated in my laboratory, including models of arousal from vaginal and clitoral engorgement, full and partial sexual solicitations as models of sexual desire, and models of orgasm from clitoral stimulation and copulation that occurs at a preferred rate for each female under her control. The proposed experiments will examine several potential pharmacotherapies currently in clinical trials, along with experientially-based therapies, to complete the validation of the behavioral models and to use them to assess neurochemical, epigenetic, and molecular mechanisms of onset and therapeutic efficacy. It is hypothesized that amelioration of sexual arousal and/or desire disorders will depend on one of two common mechanisms: the activation of one or more excitatory brain neurochemical pathways, including dopamine, noradrenaline, along with important reward induced by pleasurable opioid activation, or the inhibition of inhibitory pathways driven largely by serotonin. The goal of this project is to generate a neurochemical model of different female sexual dysfunctions that can be used to create rational pharmacotherapies or examine as causal mechanisms in conjunction with behavioral endpoints in experientially-based interventions.