On the role of adenosine (A)₂A receptors in cocaine-induced reward: a pharmacological and neurochemical analysis in rats.

rationaleSeveral studies have suggested the inhibitory control of adenosine (A)2A receptor stimulation in cocaine-induced behavioral actions.

objectivesA combination of systemic or local drug injections and in vivo neurochemical analysis investigated A2A receptors in cocaine and food reward.

methodsRats, trained to self-administer cocaine or food, were tested with the selective A2A receptor antagonists KW 6002 and SCH 58261 or the selective A2A receptor agonist CGS 21680. Extracellular dopamine, glutamate, and GABA levels in the nucleus accumbens and ventral pallidum were determined following intra-accumbal CGS 21680 administration during cocaine self-administration.

resultsNeither KW 6002 nor SCH 58261 (0.25-1 mg/kg) altered cocaine self-administration (0.125-0.5 mg/kg/infusion), while CGS 21680 (0.2-0.4 mg/kg) produced a downward shift in the cocaine dose-response curve under a fixed ratio schedule of reinforcement and decreased the cocaine breaking point. CGS 21680 blocked also operant responding for food, while the A2A receptor antagonists were inactive. Local steady-state infusion of CGS 21680 (10 μM) during cocaine self-administration increased the active level pressing that was accompanied with reduced dopamine and increased GABA in the nucleus accumbens in the absence of changes in GABA and glutamate levels in the ventral pallidum. Pretreatment with systemic KW 6002 counteracted the increases in number of cocaine infusions seen after intra-accumbal administration of CGS 21680.

conclusionThe findings support a role of A2A receptors in modulating goal-maintained behaviors. They also indicate that increased accumbal GABA release involving an antagonistic A2A-D2 receptor interaction can participate in mediating the inhibitory effects of the A2A agonist on cocaine reward.