Project III: Clinical Studies of Cocaine-Endocrine Interactions is part of a new application of a NIDA Program Project (P01) entitled Cocaine and Polydrug Abuse: New Medication Strategies. Clinical and preclinical studies suggest that the endocrine system may influence the abuse- related effects of cocaine. These findings predict that an increased understanding of cocaine's acute effects on anterior pituitary, gonadal and adrenal hormones will suggests new strategies for the development of anti-cocaine medications. We propose to conduct clinical studies of the acute effects of cocaine on the hypothalamic-pituitary-adrenal axis (HPA) and the hypothalamic- pituitary-gonadal axis (HPG) in men. and women with a history of cocaine abuse (DSM-IV criteria). Women will be studied at the mid- follicular and the mid-luteal phase pf the menstrual cycle to determine if hormone fluctuations across the menstrual cycle influence the endocrine, subjective and cardiovascular effects of cocaine. Although the pharmacokinetic profiles of cocaine were equivalent in men and women in our previous clinical studies, unexpected gender differences in cocaine's hormonal effects have just been discovered. Because both pharmacodynamic and pharmacokinetic factors can influence medication efficacy, we propose to conduct clinical studies of cocaine's endocrine profile in relation to its subjective and cardiovascular effects. Specifically, we propose to focus on the rapid hormonal changes that parallel the rapid rise in plasma cocaine levels after i.v. cocaine injection. There is considerable evidence that cocaine stimulates the HPA axis, and this has led to one of the biological approaches to treatment proposed in Project V: Biologic Approaches to Cocaine Abuse Treatment. However,, there have been no comprehensive studies of cocaine's effects on the HPG axis in men or in women. Yet preclinical studies have shown that gonadal steroid hormones may enhance cocaine's abuse-related effects and may contribute to gender differences in cocaine's behavioral effects. In rodents, females are more responsive to cocaine than males, and this gender difference is maximal at estrus when estradiol levels are high. Moreover, estradiol and testosterone have mood elevating effects in men and women. We propose to study the temporal relations between cocaine's gonadal steroid hormone effects and subjective and cardiovascular effects in men and in women at two phase of the menstrual cycle. The pharmacological mechanisms subserving cocaine's hormonal effects will be analyzed in related preclinical studies in Project IV: Neuroendocrine Approaches to Anti-Cocaine Medications. Taken together, these collaborative inter-related clinical and pre-clinical studies should increase our understanding of one aspect of neurobiology of cocaine abuse and lead to further biologic approaches to anti-cocaine medications as are proposed for study in Project V.
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