?-Arrestin 2 knockout mice exhibit sensitized dopamine release and increased reward in response to a low dose of alcohol.

ABSTRACT: RATIONALE:The rewarding effects of alcohol have been attributed to interactions between opioid and dopaminergic system within the mesolimbic reward pathway. We have previously shown that ablation of ?-arrestin 2 (Arrb2), a crucial regulator of ?-opioid receptor function, attenuates alcohol-induced hyperlocomotion and c-fos activation in the nucleus accumbens. OBJECTIVES:Here, we further investigated the role of Arrb2 in modulating alcohol-induced dopamine (DA) release and conditioned place preference (CPP). We also assessed the functional importance of Arrb2 for ?-opioid receptor surface expression and signaling following an acute alcohol challenge. METHODS:Alcohol-evoked (0.375, 0.75, and 1.5 g/kg intraperitoneally) DA release was measured by in vivo microdialysis in the shell of nucleus accumbens. Reward was assessed by the CPP paradigm. Receptor function was assessed by ?-receptor binding and [(35)S]GTP-?-S autoradiography. RESULTS:In Arrb2 knockout mice accumbal DA levels reach maximum response at a lower dose compared to wild-type (wt) animals. In line with these results, Arrb2 knockout mice display increased CPP for alcohol as compared to wt mice. Finally, Arrb2 mutant mice display increased ?-opioid receptor signaling in the ventral and dorsal striatum and amygdala in response to a low dose of alcohol, indicating impaired desensitization mechanisms in these mice. CONCLUSIONS:Our results show that Arrb2 modulates the response to low doses of alcohol on various levels including ?-opioid receptor signaling, DA release, and reward. They also reveal a clear dissociation between the effects of Arrb2 on psychomotor and reward behaviors.

SUBMITTER: Bjork K 

PROVIDER: S-EPMC3817962 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature