Cocaine has become a major drug of abuse in our society. Unfortunately, very little is known about the possible deleterious effects of this drug on reproductive functions. On the other hand, cocaine is known to inhibit aminergic neurotransmitter reuptake in the brain and thus alter the activities of these neurotransmitter systems. Because several of these aminergic systems play central roles in regulating cyclic reproductive functions, it is reasonable to postulate that cocaine would disrupt those functions. This is supported by clinical case studies documenting the association of chronic cocaine abuse with reproductive dysfunction in humans, including disruption of normal menstrual cyclicity and decreased libido. Our preliminary studies demonstrate that cocaine administration does disrupt estrous cyclicity and normal rates of ovulation in rats. Additionally, our preliminary in vitro studies demonstrate that both GnRH and aminergic release from the hypothalami of cocaine-treated rats is significantly altered. These observations have led to the central hypothesis of this proposal that cocaine induces female reproductive dysfunction by interrupting pulsatile GnRH release from the hypothalamus. The proposed studies will extend and confirm our preliminary findings that cocaine disrupts estrous cyclicity and ovulation rates in the rat. These studies will include dose-response effects of cocaine on estrous cyclicity and normal rates of ovulation as well as examination of the effects of acute cocaine exposure given at different estrous cycle stages on circulating luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and ovulation rates. In vivo perfusion studies will allow us to selectively examine the effects of cocaine on hypothalamic functions integral to the regulation of cyclic reproduction, ie., the effects of cocaine on the peak frequency and amplitude of stimulated aminergic and GnRH release in vitro. We also recognize that cocaine's disruptive reproductive effects may result from an interaction at one or more levels of the hypothalamo-pituitary- ovarian axis. We will therefore examine the ability of GnRH replacement to restore estrous cyclicity and normal ovulation rates in cocaine treated female rats. We will examine the effects of cocaine on in vitro GnRH-stimulated pituitary LH (and FSH) secretion. Finally, we will examine the effects of cocaine on exogenous hormone-induced ovulation in sexually immature female rats. Thus, the proposed studies will define cocaine's effects on the hypothalamus, pituitary and ovary and thus elucidate the disruptive effects of this drug on cyclic reproductive function. Such information will be of tremendous value for the clinical management of cyclic reproductive dysfunction, including endocrine-related psychiatric disorders, related to cocaine abuse.