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Psychopharmacology

, Volume 230, Issue 3, pp 439–449 | Cite as

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

  • Karl Björk
  • Valeria Tronci
  • Annika Thorsell
  • Gianluigi Tanda
  • Natalie Hirth
  • Markus Heilig
  • Anita C. Hansson
  • Wolfgang H. Sommer
Original Investigation

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 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.

Keywords

Arrestin Opioid Dopamine Alcohol Reward Nucleus accumbens 

Notes

Acknowledgments

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.

Supplementary material

213_2013_3166_MOESM1_ESM.docx (18 kb)
ESM 1 (DOCX 17 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Karl Björk
    • 1
    • 3
    • 6
  • Valeria Tronci
    • 2
  • Annika Thorsell
    • 3
    • 4
  • Gianluigi Tanda
    • 2
  • Natalie Hirth
    • 5
  • Markus Heilig
    • 3
  • Anita C. Hansson
    • 3
    • 5
  • Wolfgang H. Sommer
    • 3
    • 5
  1. 1.Translational Neuropharmacology, Department of Clinical NeuroscienceKarolinska InstituteStockholmSweden
  2. 2.Psychobiology SectionNIDA, National Institutes of HealthBaltimoreUSA
  3. 3.Laboratory of Clinical and Translational Studies, NIAAANational Institutes of HealthBethesdaUSA
  4. 4.Department of Clinical and Experimental MedicineLinköping UniversityLinköpingSweden
  5. 5.Institute of Psychopharmacology at Central Institute of Mental Health, Medical Faculty MannheimUniversity of HeidelbergMannheimGermany
  6. 6.Karolinska Institute, Center for Molecular Medicine, Section for Translational NeuropharmacologyL8:01 Karolinska University HospitalStockholmSweden

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