Evidence suggests that the discriminative stimulus properties of cocaine are related to factors involved in its self-administration. Drugs that share stimulus properties with cocaine might be useful clinically for the treatment of cocaine withdrawal and symptoms of drug-craving. Historically, drugs that share stimulus properties with cocaine have abuse potential of their own (e.g., amphetamine, methylphenidate). However, recently it has been found that the discriminative stimulus properties of cocaine generalize to adrenergic compounds such as the norepinephrine uptake inhibitor desipramine, the beta adrenergic agonist clenbuterol, and the alpha adrenergic agonist clonidine. This is particularly exciting in light of recent clinical studies indicating that desipramine is able to reduce drug craving associated with cocaine withdrawal. Thus, it is of interest to characterize more extensively the role of noradrenergic systems in the stimulus properties of cocaine. The proposed studies, using rats, will determine: 1. Whether additional adrenergic drugs will substitute for cocaine in cocaine-saline discriminating rats and whether selective adrenergic receptor antagonists will inhibit this substitution, 2. Whether the ability of adrenergic drugs to substitute for cocaine will persist with chronic drug administration such that the stimulus properties of cocaine are fully and perhaps irreversibly transferred from cocaine to the substituted adrenergic drug, 3. Whether selective lesioning of dopaminergic or noradrenergic neurons alters the discriminative stimulus properties of cocaine or the ability of adrenergic drugs to substitute for cocaine, and 4. Whether the interaction of adrenergic drugs with 3H-cocaine binding sites in brain is related to their ability to share stimulus properties with cocaine. The results of the proposed studies will provide basic information on the contribution of noradrenergic systems in the stimulus properties of cocaine. Moreover, these results may have clinical relevance for the pharmacological treatment of cocaine abuse.
