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β-Arrestin 2 knockout mice exhibit sensitized dopamine release and increased reward in response to a low dose of alcohol
Karolinska Institute, Stockholm, Sweden .
Psychobiology Section, NIDA, National Institutes of Health, Baltimore, MD, USA .
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. (Centrum för social och affektiv neurovetenskap (CSAN))
Psychobiology Section, NIDA, National Institutes of Health, Baltimore, MD, USA .
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2013 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 230, no 3, 439-449 p.Article in journal (Refereed) Published
Abstract [en]

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 β-arrestin 2 (Arrb2), a crucial regulator of μ-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 μ-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 μ-receptor binding and [35S]GTP-γ-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 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.

Conclusions

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.

Place, publisher, year, edition, pages
Springer, 2013. Vol. 230, no 3, 439-449 p.
Keyword [en]
arrestin, conditioned place preference, dopamine, reward
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-94653DOI: 10.1007/s00213-013-3166-xISI: 000327090500010PubMedID: 23779257OAI: oai:DiVA.org:liu-94653DiVA: diva2:634186
Available from: 2013-06-28 Created: 2013-06-28 Last updated: 2017-12-06Bibliographically approved

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Thorsell, AnnikaHeilig, Markus

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