The most difficult aspect of treating cocaine abusers is their propensity to relapse to cocaine use after some period of abstinence. Cocaine abusers often describe their relapse as being precipitated by cocaine Craving, which might be triggered by a """"""""priming"""""""" dose of cocaine itself. The reinforcing effects of cocaine are believed to be partly mediated by the effect of cocaine on dopamine (DA) release in the ventral striatum. Studies in laboratory animals have shown that low dose cocaine can trigger """"""""relapse"""""""" in an animal model of cocaine-seeking behavior. In this model, D2 receptor agonists share with cocaine the property of stimulating cocaine-seeking behavior, while Dl receptor agonists do not. Moreover, D1 agonists prevent the priming effect of cocaine on cocaine-seeking behavior. If these rodent data are relevant to humans, one could expect that the respective intensity of D2 and Di stimulation following a priming dose of cocaine might play a role in the intensity of subsequent self administration. In addition, studies in primates have shown that chronic cocaine self-administration leads to a reduction of Di receptor density in the ventral striatum, a phenomenon that might contribute to the increased vulnerability of chronic cocaine abusers to cocaine-induced relapse. Previous imaging studies demonstrated that chronic cocaine abuse is associated with reduction of D2 receptor density in the striatum, but the impact of chronic cocaine use and Di density has not been studied in vivo in humans. In this application, we propose to measure with PET both Di receptors (using [1lC]NNC 112) and D2 receptors (using [l8F]fallypride) in 36 chronic cocaine users and 36 matched controls, to test the hypothesis that Dl and D2 receptors are selectively reduced in the ventral striatum in cocaine abusers. Furthermore, we propose to test the hypothesis that reduced Dl to D2 receptor ratio in the ventral striatum is associated with increased vulnerability to cocaine induced cocaine self-administration. We have developed in our laboratory a cocaine self-administration paradigm that enables measurement of cocaine self-administration following administration of a low dose of cocaine (""""""""priming"""""""" dose). Thus, the unique aspect of this proposal is the combination of state-of-the-art PET technology and established laboratory methods for studying cocaine self- administration. Development of medications for the treatment of cocaine abuse will benefit from a better understanding of the biological factors underlying vulnerability to relapse, and this study has the potential to provide a biological marker of relapse vulnerability, that could be used in subsequent clinical trials of D1 agonists.
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