Repeated exposure to low doses of nicotine produces increased responsiveness to the stimulatory effects of nicotine and prolonged elevations in the number of nicotine receptors in the brain. These phenomena are likely to be important aspects of the process of developing and maintaining a dependence on nicotine. This project will use several experimental approaches to further our understanding of nicotine as a behavioral stimulant and as a drug of dependence. One series of studies will employ lesion, pharmacological blockade, and localized intracerebral microinfusions to test the hypothesis that nicotine exerts its stimulant actions in rats through the mesolimbic dopamine pathway. This pathway has been widely studied as a neural substrate for the stimulant actions of amphetamine, cocaine, and the opiates. We will also train rats to self-administer nicotine, to determine whether previous experience with nicotine increases the reinforcing properties of the first self-administered doses. Our previous research demonstrates that rats allowed to drink nicotine solutions will increase their intake over days and show altered behavioral reactions to orally infused nicotine solutions (increased ingestive behaviors). Several experiments usinq two-bottle preference tests and taste reactivity to oral infusions will test whether the increased intake seen with experience is related to the reinforcing properties of the ingested nicotine or to a diminished aversive reaction to the sensory properties of the solutions. Understanding the behavioral neuropharmacoloqy of nicotine dependence is important for two reasons. First, tobacco dependence is responsible for more American deaths each year than all other forms of drug dependence combined. Second, both the brain systems under investigation and the techniques to be employed are of importance for understanding other drugs of abuse.