The Trans-NIH Mouse Initiative is now underway for developing new, cost-effective, high throughput phenotyping techniques to assess specific components of central nervous system function in inbred strains of laboratory mice. One purpose for developing such techniques is to apply this technology to mutant mice; with the expectation that the genetic analysis of complex traits will be facilitated and that basic brain processes and diseases of the central nervous system will be better understood and treated. Numerous mouse knockouts now exist, but little is known regarding the functional significance of their altered genetics. There are many complex behaviors of interest in the Trans-NIH Mouse Initiative; among them are cognition, learning and memory, and the taking and seeking of drugs of abuse. The goal of this research is to develop a new method of cocaine self-administration that can be used long-term in inbred and genetic knockout strains of mice to simulate the full array of human behaviors or experiences associated with drug addiction. These include the acquisition, maintenance, extinction and reinstatement of drug-seeking and drug-taking behavior. The present proposal seeks to develop a method of cocaine self-administration whereby a discrete dose of aerosolized cocaine is intermittently delivered to a sniff port after a nose-poke response, thus avoiding many of the limitations imposed by previous methods. There are three specific aims to accomplish this goal: (1) Design an apparatus that can reliably deliver a discrete dose of aerosolized cocaine on an intermittent basis; (2) Develop and validate this inhalation method of cocaine self-administration in an inbred mouse strain by training mice to nose pole for cocaine delivery and by varying both the dose of inhaled cocaine and the response requirements necessary for obtaining it; (3) Apply this method in inbred and genetic knockout strains of mice by studying the effects of nitric oxide synthase deficiency on the acquisition, maintenance , extinction and reinstatement of cocaine-seeking and cocaine self-administration in neuronal NOS knockout mice and in inbred strains of mice after NOS inhibitor treatment.