The unifying theme of this application is the use of a multidisciplinary approach to study reinforcing efficacy polydrug abuse and potential pharmacological treatments for drug abuse. Operant behavioral techniques and measures of electrophysiological activity will be employed in experiments that utilize both rhesus monkeys and human volunteers as subjects. The behavioral pharmacology of buprenorphine, an opioid mixed agonist/antagonist analgesic, will be studied in a primate drug self-administration model. This research is designed to evaluate the neurobiological aspects of buprenorphine's and related compound's reinforcing properties using progressive ratio procedures. A second goal of this study is to determine the effects of buprenorphine and naltrexone maintenance on self- administration of opiates, cocaine, methohexital, and triazolam. A second preclinical study is designed to evaluate desipramine as a potential pharmacotherapy for cocaine abuse. The proposed clinical studies are aimed at studying polydrug abuse, tolerance to marihuana and ethanol effects, vulnerability to ethanol effects, and the neurophysiological indices of prenatal exposure to ethanol. The first study will evaluate the consequences of concurrent administration of cocaine, marihuana, and ethanol using electrophysiological and behavioral measures. Changes in spontaneous EEG activity and P300 evoked potential responses obtained during performance of psychomotor tasks will be correlated with subjective reports of intoxication. These studies will employ two different strategies for uncovering the biobehavioral and pharmacologic profiles of drug abuse: acute drug interactions, and drug self-administration. Studies of the genetic and environmental factors that contribute to an individual's sensitivity to ethanol effects will be conducted using similar procedures. Finally, a study is planned to determine if young boys who were exposed to ethanol in utero can be identified by changes in topographic brain electrical activity and performance on psychomotor tasks. Results from these studies may improve our understanding of the factors that contribute to a drug's reinforcing properties and how these effects are modified by other drugs. Such information may be helpful in identifying risk factors for drug abuse as well as the design of new treatments.
