ENVIRONMENTAL INFLUENCES ON COCAINE SELF ADMINISTRATION

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This revised competing continuation application proposes to proceed with investigations of the effects of environmental-stress and the subsequent activation of the HPA axis on the initiation and maintenance of intravenous cocaine self-administration in rats. The primary hypothesis underlying these experiments is that the reinforcing and subjective effects of cocaine are mediated, at least in part, through interactions with common neurobiological effector systems also activated by stress. Data collected to date have demonstrated an important role for corticosterone in cocaine reinforcement, and preliminary data suggest that it is the actions of this hormone at glucocorticoid or Type II adrenocorticosteroid receptors that are responsible for this effect. The first experiments will investigate the effects of adrenocorticosteroids on responding under an alternating, multiple schedule of food reinforcement and cocaine self-administration to determine if the effects of adrenocorticosteroids on intravenous cocaine self-administration are the result of specific actions on cocaine reinforcement or nonspecific effects on the ability of the rats to respond. Follow-up experiments will also investigate the role for adrenocorticosteroids in the acquisition of intravenous cocaine self- administration in rats. Finally, experiments are proposed that will determine whether or not adreno-corticosteroids are also involved in the increased sensitivity to cocaine observed in rats exposed to stress. Another series of experiments will investigate the effects of adrenocorticosteroids in the reinstatement of intravenous cocaine self- administration to determine the effects of adrenocorticosteroids in this animal model of craving. Drugs which are effective in blocking the electric footshock and/or cocaine-induced reinstatement of cocaine-seeking behavior may also be effective in alleviating symptoms of cocaine craving in humans. Other experiments will investigate the effects of stress and adrenocorticosteroids in the discriminative stimulus effects of cocaine to determine whether or not the subjective and reinforcing effects of cocaine are mediated through similar mechanisms. These experiments will increase knowledge of how stress and the subsequent activation of the HPA axis influence cocaine reinforcement and may also suggest novel pharmacotherapies for the treatment of cocaine abuse and withdrawal in humans.