The research program outlined in this proposal supports the application for renewal of a Research Scientist Award to Dr. Sam A. Deadwyler, Professor of Physiology, Bowman Gray School of Medicine. The objectives of the research to be conducted over the five year period of the award are directed toward establishing the acute and chronic effects of exposure to cannabinoids and cannabimimetic substances as well as the neural effects of cocaine and psychomotor stimulants. Four different individual research projects are supported in this program, each of which deals with a separate issue concerning cannabinoid and/or cocaine action in specific brain regions. Two of the projects are concerned with the actions of cannabinoids and recently developed cannabinoid analogs in the hippocampus and related brain regions, under acute and chronic exposure conditions. It has been firmly established in the preceding period of this award that cannabinoid receptors in the hippocampus play a major role in memory processing and that long term exposure to these substances produces a considerable degree of tolerance to the initial disruptive effects. The research strategy in this application seeks to understand the mechanisms of cannabinoid disruption of memory processes in terms of both the cellular and neural circuit components of memory formation in the hippocampus. A third project examines the effects of cannabinoid and cannabinoid analogs on individual cellular mechanisms in order to determine precisely the conductance changes effected by cannabinoid receptor occupancy. In the past period of the award it has been discovered by the candidate that there are at least 2 candidates for this effect, increased potassium conductance, and increased chloride conductance on hippocampal and cortical neurones. A third possibility, decreased calcium conductance was reported also in a separate laboratory. The fourth and most recent project in the research program deals with the electrophysiological investigation of neural correlates of cocaine self-administration in rats. This project applies technology developed in the first two projects on hippocampal investigation in vivo to an analysis of many neurone activity in the nucleus accumbens and ventral tegmental dopamine cells in rats trained to self-administer cocaine. This project is primarily concerned with the elucidation of the neural processes underlying the rewarding properties of psychomotor stimulants and the neurophysiological relationship between these structures and the hippocampus, a major source of afferent projections to the nucleus accumbens. The award will allow Dr. Deadwyler to continue to devote maximal effort to the above research objectives, freeing him from otherwise conflicting departmental duties and teaching responsibilities. In addition it will provide the opportunity for him to make extensive visits to other laboratories for the purpose of establishing new techniques and collaborative arrangements not available in the current environment.