title: β-Arrestin 2 knockout mice exhibit sensitized dopamine release and increased reward in response to a low dose of alcohol.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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 [(35)S]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.
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden, karl.bjork@ki.se.
authors.forename: Karl
authors.initials: K
authors.lastname: Björk
authors.forename: Valeria
authors.initials: V
authors.lastname: Tronci
authors.forename: Annika
authors.initials: A
authors.lastname: Thorsell
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Tanda
authors.forename: Natalie
authors.initials: N
authors.lastname: Hirth
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
authors.forename: Anita C
authors.initials: AC
authors.lastname: Hansson
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Sommer
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D019390:Arrestins / Q000235:genetics*; D001345:Autoradiography; D003213:Conditioning, Psychological / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D012201:Reward; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605258:Arrb2 protein, mouse; D019390:Arrestins; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000431:Ethanol; D004298:Dopamine