Increase in A 2A receptors in the nucleus accumbens after extended cocaine self-administration and its disappearance after cocaine withdrawal

Abstract

Effects of extended cocaine self-administration and its withdrawal have been studied on A 2A and D 2 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 D 2-like receptor antagonist radioligand [ 3H]-Raclopride and the A 2A receptor antagonist radioligand [ 3H]-ZM 241385 and immunoblots to study their expression. A substantial and significant increase in functional A 2A, but not in functional D 2 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 A 2A expression were observed immediately after cocaine self-administration which was associated with a trend for a reduction of the A 2A receptor antagonist binding sites. In cocaine withdrawal groups, significant increases in the density and K d value of D 2-like antagonist binding sites were observed in the nucleus accumbens in the absence of changes in D 2 expression, suggesting an up-regulation of D 3 receptors in this region after cocaine withdrawal. A 2A receptor increases in the nucleus accumbens induced by cocaine may represent a compensatory up-regulation to counteract cocaine-induced increases in D 2 signaling and D 3 signaling which is in line with its disappearance in the 7-day withdrawal group displaying increased reinforcing efficacy of cocaine. A 2A agonists may therefore represent cocaine antagonist drugs to be used in treatment of cocaine addiction acting inter alia by antagonizing signaling in accumbens A 2A/D 2 and A 2A/D 3 heteromers.