Heroin, cocaine, and alcohol addictions, alone and in various combinations of codependency, often withcomorbidity and other major medical complications, especially hepatitis C and AIDS, remain major personaland public health problems confronting our nation and the world. Bidirectional translational research, whichwill be accomplished by interactions among Projects 1, 2, and 3 herein and this project, will allow theexpansion of a fundamental understanding of the dynamic molecular neurobiology of specific addictivediseases in stages prior to andduring treatment of a pharmacological or behavioral type. This project willexplore the atypical stress responsivity of the hypothalamic-pituitary-adrenal (HPA) axis seen in untreatedaddictive diseases, including the contributions of the opioid system in the modulation of that axis andinteractions with the dopaminergic and glutamatergic systems. Several hypotheses will be tested: 1.1) thatbuprenorphine, a partial mu agonist with some kappa opioid receptor activity, will permit normalization of theHPA axis; 1.2) that the regulation of anterior pituitary by arginine vasopressin, a possible target for noveltherapeutic intervention, becomes altered during cycles of addiction and normalizes during effectivetreatment; and 1.3) that restoration of normal HPA axis function will occur slowly in cocaine addictseffectively managed with behavioral treatment; 2) that untreated cocaine dependency, with concurrentalcohol or opioid abuse or dependency, will result in significant alterations in normal stress.responsivity; 3)that alterations of stress responsivity will normalize during effective treatment for depression; and 4) thatresponses to challenge or provocative tests may be different, and even basal levels of hormone may bedifferent, in persons with a specific functional or possibly functional gene variant, or a variant or haplotype, a)associated with an addiction or b) of a gene whose expression is altered by chronic exposure to cocaine orheroin may be related to basal or test response hormone levels. The role of the endogenous opioid system,and other specific components of the HPA axis will be studied with standard and novel challengecompounds, and combinations thereof, including CRF, arginine vasopressin, synthetic ACTH, metyrapone,opioid antagonists dynorphin A(1-13) in patients with specific addictive diseases and normalvolunteers.
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