Cocaine use and dependence exact a considerable toll, not only to the individual user, but also to the community at large because the cocaine-driven behavior of the user causes a wide range of economic, biomedical and social problems, including crime, spread of infectious disease, and neonatal drug exposure. Currently there are no recommended drug therapies for cocaine dependence, although the need is great. Functional characteristics of the neurotransmitter neuropeptide Y (NPY) suggest that the development of medicinal drugs that target NPY neurotransmission will be effective in reducing cocaine craving and mood disturbances during periods of abstinence. Craving, anxiety, and depression during periods of cocaine abstinence underlie relapse. The research proposed here will test the effectiveness of NPY agonists (drugs that stimulate NPY activity) to reduce craving and heightened anxiety that occur during short (1 week) and long (3 week) periods of abstinence from cocaine in an animal model of cocaine dependence. To assess craving, rats will be tested in a place preference apparatus in which they will be trained to associate a particular place (a neutral environment) with a daily cocaine treatment. During periods of cocaine abstinence, the rat's preference to go to and remain in the place they previously received cocaine (""""""""the neutral environment"""""""") will provide an indirect measure of cocaine seeking (craving). The effect of increasing NPY activity in the brain during periods of cocaine abstinence on place preference will be used to assess the effect of NPY on cue-induced cocaine seeking. Additionally, the interaction between NPY and a predator stress (exposure to a cat-scented cloth) on place preference, or the interaction between NPY and a subsequent exposure to cocaine on place preference, will be assessed to determine if NPY blocks stressand drug-induced increases in cocaine seeking. Finally, the impact of NPY on cocaine withdrawal will be assessed by evaluating the ability of NPY to suppress the heightened anxiety associated with the first 48 hrs of abstinence. The results will add to our understanding of the neurobiological substrates that underlie cocaine dependence and indicate whether or not the pursuit of medicinal compounds that target NPY neurotransmission is warranted for the purpose of managing cocaine dependence.
