This is a proposal to launch a major research project involving drugs of abuse. The primary objective is to put together an interdisciplinary research team capable of mounting a concerted attack on drug abuse problems. In addition, the project will serve as a training base for new and mature scientists who wish to gain experience in the field. Our initial efforts will be concentrated in two areas, narcotics and narcotic antagonists, and marihuana. We will continue and greatly expand our studies into the basic mechanisms involved in the tolerance seen both with the narcotics and the tetra-hydrocannabinols. Also included will be studies directed toward the elucidation of the mechanism involved with physical dependence and withdrawal. We will be looking for new models of drug seeking behavior and factors which influence this behavior. The development of new, more effective narcotic antagonists and their evaluation in the therapy of narcotic abuse will be a prominent part of the program. Finally, basic kinetic and metabolic studies will be carried out in animals and man which may help in the rational use of these drugs as well as the prevention and treatment of their abuse.