Heroin, cocaine, and alcohol addictions, alone and in combination, along with their medical complications, including hepatitis B and C, AIDS, and psychiatric comorbidity, remain the major medical problems confronting our nation and much of the world. Effective treatments must be based on a fundamental understanding of the biological basis of each addictive disease, including the effects of exposure to drugs of abuse. This Project will continue to explore the atypical stress responsivity of the hypothalamic-pituitary-adrenal (HPA) axis seen in specific addictive diseases. Contributions of opioid and dopaminergic pathophysiological mechanisms will also be investigated. The specific hypotheses are: 1) that chronic cocaine addiction causes alterations in stress-responsive HPA axis function; 2) that alterations in HPA axis function caused by cocaine may be further modulated by alcohol abuse and/or opiate dependence; 3) that the relationship between cocaine addiction and alterations in HPA axis function is controlled in part by the endogenous opioid system; 4) that the regulation and release of corticotropin releasing factor (CRF) and proopiomelanocortin (POMC; and its peptide fragments including ACTH and beta-endorphin) are, in part, under the control of the endogenous opioid system and that changes in the sensitivity of the CRF-R1 receptor in the anterior pituitary are central to the atypical stress responsivity seen in different stages of addiction; 5) that psychological states which are believed to be both stress-related and important in the development and maintenance of addictions, may occur through alterations in HPA axis function and the endogenous opioid system; and 6) that the observed alterations in the physiology of the endogenous opioid system and its interactions with the stress-responsive HPA axis in addictive diseases may, in part, be influenced by specific single nucleotide and other polymorphisms in genes of the endogenous opioid system. The hypotheses will be explored using standard and novel paradigms of HPA disinhibition (by metyrapone and dexamethasone) and stimulation (by ACTH and CRF) testing alone and in combination. The role of the endogenous opioid system in affecting the HPA axis will be studied with opioid antagonists alone and in combination with HPA axis testing. This work, to be performed in patients with specific addictions and normal volunteers, will complement rodent and non-human primate studies conducted in our Center.