Heroin, cocaine and alcohol addiction with their frequent complications including hepatitis B, C, non-A, non-B and Delta, cirrhosis, and AIDS to psychiatric and sociopathic disorders, remain the major medical problems confronting our nation. Effective treatments based on a fundamental understanding of the biological basis of addictive diseases, the effects of drugs of abuse, and of pharmacological agents used or potentially useful in the treatment of drug abuse, as well as information about approaches to the management of the medical and behavioral problems which may complicate treatment, are still urgently needed. Our Treatment Research Center will continue to identify and study the biological correlates of addictions, and as a major part of this effort, to study factors which affect treatment outcome. Pharmacological, metabolic, medical, and behavioral problems which complicate treatment will be studied. In this proposal for continuation of our Center, all laboratory and clinical research studies are developed on an interactive basis, relying upon the Center for their integration. Six continuing projects are: 1) to study further the disposition, metabolism, processing, and interactions of exogenous and endogenous opioids and their antagonists, developing novel techniques of laser desorption mass spectrometry to study opioids and neuropeptides; 2) to define the effects of selected drugs of abuse and treatment agents on neuroendocrine function and to examine the relationship of atypical responsivity to induced stress which we have previously observed in preliminary studies, demonstrated in heroin and cocaine addicts to the clinical phenomenon of craving and relapse; 3) to further study the endogenous opioid system of the gastrointestinal tract and its relationship to that of the brain, and to extend clinical studies of an opioid antagonist with limited systemic bioavailability for the management of opiate induced gastrointestinal disorders; 4) to extend studies on the molecular biology of the viroid-like Delta agent, and to explore the use of custom constructed oligonucleotide ribozymes to destroy the Delta agent and also to cleave selected mRNAs: 5) to study further mechanisms involved in control of enkephalin gene expression in the hamster adrenal medulla. Three are new projects: 6) to study the effects of cocaine, morphine, alcohol and potential treatment agents on opioid receptors and peptides; 7) in parallel, to study the effects of drugs of abuse and treatment agents on opioid gene expression using the sensitive technique of solution hybridization protection assays for quantitation of mRNAs. These scientific projects will be integrated through the Core Laboratory and Clinical Resources, strengthening interactions which only a Research Center can provide, an advantage which has been documented during the first four years of this Research Center.