Project V: Biologic Approaches to Cocaine Abuse Treatment is part of a new application for a NIDA Program Project (P-01) entitled Cocaine and Polydrug Abuse: New Medication Strategies. Two series of studies are proposed to test the hypothesis that endocrine and neuroendocrine systems may be useful targets for the development of novel medication strategies for cocaine abuse. The first series of studies is based on our discovery that administration of synthetic luteinizing hormone releasing hormone (LHRH) not only increased plasma levels of luteinizing hormone (LH), but also dose-dependently decreased peak plasma levels of free (unbound) cocaine in both rhesus monkeys and humans following i.v. cocaine injection. he LH glycoprotein molecule shares structural features with other cocaine binding substrates including the dopamine transporter, and plasma levels of circulating glycoproteins (e.g., alpha- acid glycoprotein) are known to bind to cocaine and influence levels of free cocaine in plasma. In pharmacokinetic studies in rats, we will assess the ability of synthetic LHRH injections to alter plasma and brain levels of cocaine after i.v. administration. In complementary behavioral studies, we will evaluate the effects of synthetic LHRH on both cocaine discrimination and cocaine self-administration in rhesus monkeys. If our hypothesis is correct, increased LHRH levels will reduce brain levels of cocaine in rats and cocaine's abuse-related effects in monkeys. Such findings would encourage further studies to identify the relevant subunit of the LH glycoprotein that binds to cocaine, and may provide a new approach to the development of anti-cocaine medications. A second series of studies is based on our recent findings that acute administration of cocaine stimulates an immediate release of adrenocorticotropin hormone (ACTH) from the anterior pituitary and a subsequent release of cortisol from the adrenal gland in rhesus monkeys and in humans (Projects III and IV). Clinical reports of a significant temporal concordance between increased plasma cocaine levels, cocaine- induced increases in ACTH and subjective reports of cocaine-induced """"""""high"""""""" further suggest that the hypothalamic-pituitary adrenal (HPA) axis may contribute to cocaine's abuse-related effects. Using newly available systematically-active CRF antagonists, we will test the hypothesis that activation of HPA systems contributes to cocaine's discriminative stimulus and reinforcing effects in rats and monkeys. Additional studies in rats will compare peptidic and non-peptidic CRF antagonists after central and systemic administration to assess pharmacokinetics and to identify brain and/or pituitary regions involved in the putative anti-cocaine effects of CRF antagonists. In these basic neurobiological and pharmacological studies, experimental designs (e.g., doses and time course of cocaine, LHRH and CRF antagonists) will be based, in par, on findings from Projects II-IV. Collectively, these studies will complement findings from other inter- related projects on cocaine's influence on endocrine function and will address the question of whether endocrine and/or neuroendocrine systems may be manipulated to attenuate cocaine's abuse-related effects and/or strengthen anti-cocaine effects of other candidate treatment medications.
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