Increase in A2A receptors in the nucleus accumbens after extended cocaine self-administration and its disappearance after cocaine withdrawal

Effects of extended cocaine self-administration and its withdrawal have been studied on A2A and D2 receptor binding characteristics and expression in the nucleus accumbens and the anterior and posterior dorsal striatum of the rat (Rattus norvegicus). Biochemical binding techniques have been used with the D2-like receptor antagonist radioligand [3H]-Raclopride and the A2A receptor antagonist radioligand [3H]-ZM 241385 and immunoblots to study their expression. A substantial and significant increase in functional A2A, but not in functional D2 receptors, was observed in the nucleus accumbens immediately following 10 days of cocaine self-administration which returned to normal levels after 7 days of drug withdrawal. In contrast, in the posterior dorsal striatum significant reductions in A2A expression were observed immediately after cocaine self-administration which was associated with a trend for a reduction of the A2A receptor antagonist binding sites. In cocaine withdrawal groups, significant increases in the density and Kd value of D2-like antagonist binding sites were observed in the nucleus accumbens in the absence of changes in D2 expression, suggesting an up-regulation of D3 receptors in this region after cocaine withdrawal. A2A receptor increases in the nucleus accumbens induced by cocaine may represent a compensatory up-regulation to counteract cocaine-induced increases in D2 signaling and D3 signaling which is in line with its disappearance in the 7-day withdrawal group displaying increased reinforcing efficacy of cocaine. A2A agonists may therefore represent cocaine antagonist drugs to be used in treatment of cocaine addiction acting inter alia by antagonizing signaling in accumbens A2A/D2 and A2A/D3 heteromers.