Cocaine dependence is a severe health problem with significant medical and societal impact. Little progress has been made in treatment, as relapse rates remain high, particularly among patients with persisting withdrawal symptoms. Anxiety during withdrawal may significantly contribute to the repetitive cycle of cocaine use, abstinence, and relapse. Anxiogenic states involve noradrenergic systems of the brain, and studies implicate norepinephrine (NE) dysfunction in cocaine withdrawal anxiety. Propranolol, a beta NE receptor antagonist, has shown promise in reducing withdrawal symptoms and promoting better treatment retention rates and less cocaine use in patients, particularly for individuals reporting severe withdrawal. Despite the connection between anxiety and relapse, no studies have carefully characterized cocaine withdrawal-induced anxiety in the most relevant preclinical animal models, in that prior studies have only used noncontingent cocaine administration. The goal of the current proposal is to develop an animal model for studying cocaine withdrawal anxiety in rats with a history of cocaine self-administration, and to use this model to study propranolol as a potential pharmacotherapy. Propranolol will be evaluated for its efficacy in alleviating withdrawal-induced anxiety, as well as preventing or reducing reinstatement of cocaine-seeking in an animal model of relapse. Furthermore, these studies will use c-fos immunolabeling to reveal potential neuronal substrates underlying cocaine withdrawal. It is hypothesized that propranolol treatment during withdrawal will be beneficial in reducing anxiety, and in combination with propranolol administered during testing, will reduce drug-seeking, with particular efficacy in blunting stress-induced reinstatement. In addition, regions of the brain previously associated with anxiety, including noradrenergic cell groups and the central and extended amygdala, are likely to be linked to withdrawal-induced anxiety. In summary, this training proposal will help reveal the behavioral, physiological, and neuronal mechanisms of cocaine withdrawal anxiety. Such data will be useful in the screening of agents which may alleviate cocaine withdrawal anxiety, as well as pharmacotherapies that show promise in decreasing drug-seeking in animal models of relapse. This translational research is highly relevant to public health issues, particularly with regard to the widespread problem of cocaine abuse and the lack of effective treatment.
