Adaptive Clinical Trial of Adenosine A2a Antagonist in Cocaine Dependence

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Chronic cocaine use may produce disruption of monoamine systems (including dopamine). This may in turn contribute to measurable dysfunction in important cognitive and behavioral processes. Pharmacotherapy with stimulants that enhance dopamine (DA) function has shown efficacy in treating cocaine dependence and improving behavioral function ~ supporting the notion that these processes are related. In the development of novel pharmacotherapies for cocaine dependence, an important step is a full understanding of the.psychopharmacological properties of potential medications for cocaine dependence, including subjective, physiological, discriminative and behavioral effects. Selective adenosine (A2A) receptor antagonists may play a key role in the modulation of DA neurotransmission by indirectly enhancing DA receptor activation. Additionally, A2A antagonists inhibit cannabinoid CBI receptor activation, suggesting a potential mechanism for reducing concurrent marijuana use in cocaine dependent patients. A2A antagonists may provide additional benefit on concurrent marijuana use in cocaine dependence, as dual cocaine-marijuana users present unique treatment challenges. This project proposes to evaluate the novel A2A antagonist SYN 115. Its stimulant-like effects may help with affective and behavioral deficiencies related to (a) DA depletion and (b) DA-CB1 interactions. Accordingly, the project aims to characterize the psychopharmacology of SYN115 in individuals with cocaine dependence, cocaine dependence with concurrent marijuana use, and controls. Employing both acute and chronic dosing designs, three experiments will be conducted using well-established psychopharmacological methods in order to characterize dose-response relationships. A mixed-model strategy will be utilized to (a) leverage the power of within-subject, repeated measures designs, and (b) compare cocaine dependent and healthy matched-control subjects. Measures will include drug discrimination, subjective effects, cardiovascular effects, behavioral inhibition (impulsivity), working memory, reversal learning, and decision making. These data will compliment and provide valuable information to our parallel clinical trials using these agents to treat cocaine dependence