Inactivation of adenosine A2A receptors selectively attenuates amphetamine-induced behavioral sensitization

Abstract

Repeated treatment with the psychostimulant amphetamine produces behavioralsensitization that may representtheneuraladaptations underlying some features of psychosis and addiction in humans. In the present study we investigated the role of adenosine A2A receptors in psychostimulant-induced locomotor sensitization using an A2A receptor knockout (A2A KO) model. Daily treatment with amphetamine for 1 week resulted in an enhanced motor response on day 8 (by two-fold compared to that on day 1), and remained enhanced at day 24 upon rechallenge with amphetamine. By contrast, locomotor sensitization to daily amphetamine did not develop in A2A KO mice on day 8 or 24, and this absence was not the result of a nonspecific threshold effect. The absence of behavioral sensitization was selective for amphetamine since daily treatment with the D1 agonist SKF81297 (2.5 mg/kg) orthe D2 agonist quinpirole (1.0 mg/kg) produced similar behavioralsensitization in both WT and A2A KO mice. Furthermore, coinjection of SKF81297 and quinpirole also resulted in indistinguishable locomotor sensitization in A2A KO and WT mice, suggesting normal D1 and D2receptor responsiveness. Finally, at the cellular levelA2A receptor inactivation abolished the increase in striataldynorphin mRNA induced by repeated amphetamine administration. The selective absence of amphetamine-induced behavioralsensitization in A2A KO mice suggests a criticalrole of the A2A receptor in the development of psychostimulant-induced behavioralsensitization, and supports the pharmacologicalpotentialof A2A adenosinergic agents to modulate adaptive responses to repeated psychostimulant exposure. © 2003 Nature Publishing Group.