β-Arrestin 2 knockout mice exhibit sensitized dopamine release and increased reward in response to a low dose of alcohol
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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 β-arrestin 2 (Arrb2), a crucial regulator of μ-opioid receptor function, attenuates alcohol-induced hyperlocomotion and c-fos activation in the nucleus accumbens.
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 μ-opioid receptor surface expression and signaling following an acute alcohol challenge.
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 μ-receptor binding and [35S]GTP-γ-S autoradiography.
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 μ-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.
Our results show that Arrb2 modulates the response to low doses of alcohol on various levels including μ-opioid receptor signaling, DA release, and reward. They also reveal a clear dissociation between the effects of Arrb2 on psychomotor and reward behaviors.
KeywordsArrestin Opioid Dopamine Alcohol Reward Nucleus accumbens
KB was supported by a grant from Svenska Stiftelsen för Medicinsk Forskning. NH and ACH were supported by a grant from the “Deutsche Forschungsgemeinschaft” (DFG, HA 6102/1). This report was also funded by the Intramural Research Programs of NIAAA and NIDA, National Institutes of Health, Department of Health and Human Services.
Conflict of interest
To the best of their knowledge, the authors do not hold financial or other interests that might be perceived as biasing the present study.
- Colasanti, A., G. E. Searle, et al. (2012). Endogenous opioid release in the human brain reward system induced by acute amphetamine administration. Biol PsychiatryGoogle Scholar
- Kranzler, H. R., S. Armeli, et al. (2012). Variation in OPRM1 moderates the effect of desire to drink on subsequent drinking and its attenuation by naltrexone treatment. Addict BiolGoogle Scholar
- Paxinos G, Franklin KBJ (2004) The mouse brain in stereotaxic coordinates. Elsevier Academic, AmsterdamGoogle Scholar