The goal of this proposal is to provide additional training and support of the applicant under the guidance of an expert in drugs in abuse and in the laboratory well equipped for electrophysiological recording in behaving animals. The candidate has medical and biological education, and extensive experience in neurophysiology and pharmacology, including dopamine (DA) systems and addictive drugs. Because of an interruption in applicant's research career and the need for additional training and supervision, this award is critically important to support his current research position and establish his future independent career. Two advanced electrophysiological techniques, single-unit recording and iontophoresis in awake, behaving rats, are combined in the proposed project with intrevenous self-administration (SA) to assess the role of mesocorticolimbic (MCL) dopamine (DA) neurons in the development and regulation of heroin-seeking and heroin-taking behavior. Although these DA neurons, located in the ventral tegmental area (VTA), play an essential role in mediating the reinforcing properties of addictive drugs and addictive behavior, the pattern of changes in MCL DA activity during natural drug-seeking and drug-taking behavior is unknown. To provide this information, three specific aims are included in this proposal: 1. To characterize electrophysiological and receptor properties of VTA units under behaviorally relevant conditions and identify presumed DA and non-DA cells; 2. To examine the pattern(s) of impulse activity of single DA and non-DA neurons in the VTA during the performance of heroin SA behavior in trained rats; and 3. To study changes in VTA cell activity associated with the initial heroin SA and the development of drug-taking behavior (first learning sessions), as well as with passive repeated heroin administration at the same dose/pattern regimen as in the SA. These experiments will provide a better understanding of the neurochemical mechanisms regulating DA cell activity and impulse-dependent DA release under natural conditions, and will clarify the role of MCL DA cells in the development and regulation of opiate addictive behavior. A better understanding of how heroin interacts with learning and behavioral variables at the level of single VTA neurons will provide unique insights into the nature of drug craving and reinforcement.
