As the overall number of smokers in the American population decreases, many of those that continue to smoke show several risk factors that make smoking cessation more difficult. Some of these risk factors may be environmental while others may have a genetic component. We propose to study the biological basis underlying how risk factors might lead to relapse to smoking. Some major predictors of treatment failure for smoking cessation include depressive symptoms, heavy alcohol use, and female gender. This proposal will use animal models to determine how nicotine affects biological processes related to these risk factors, and will focus on how activation or inhibition of neuronal nicotinic acetylcholine receptors (nAChRs) can affect behavioral and biochemical responses related to these risk factors. These experiments will make use of pharmacological studies in normal mice as well as experiments with transgenic (knock-out) mice lacking the beta2 subunit of the nAChR which have previously been generated. Existing nicotinic agonists cannot distinguish clearly between the various nicotinic subtypes present in the brain; thus these mice will be extremely useful in identifying which receptor subtypes mediate particular pharmacological actions of nicotine. The aims of this project are to determine whether nicotine can act as an antidepressant in the learned helplessness model of depression, to determine whether nicotine withdrawal increases susceptibility to learned helplessness during acute and chronic abstinence, to identify sex- differences in learned helplessness behavior with and without nicotine treatment, to determine the concurrent and independent effects of chronic ethanol and nicotine treatment on biochemical and behavioral responses to stress, and to determine whether chronic nicotine treatment results in changes in levels of second messenger proteins involved in signaling that are associated with motivation and effect. The techniques to be used include neurochemistry, molecular genetics and behavioral paradigms. These approaches should allow an integrated view of how chronic nicotine use and nicotine cessation affect emotional behavior, and how gender differences or alcohol use can modulate that interaction. These experiments will contribute to the scientific background necessary for designing new strategies for treatment of smokers resistant to current cessation methods.