Skip to main content
PMC home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2013 Jul 9;29(5):531–540. doi: 10.1007/s12264-013-1350-y

β-Arrestin-2 inhibits preference for alcohol in mice and suppresses Akt signaling in the dorsal striatum

Haohong Li 1, Yezheng Tao 1, Li Ma 1, Xing Liu 1,✉, Lan Ma 1
PMCID: PMC5561959  PMID: 23839051

Abstract

In this study, we investigated the role of β-arrestin-2 in alcohol preference using the two-bottle choice and conditioned place preference procedures in wild-type (WT) and β-arrestin-2 knockout (KO) mice. Locomotion and righting reflex tests were performed to test alcohol sensitivity. The possible molecular signals regulated by β-arrestin-2 were analyzed by Western blot. We found that β-arrestin-2 KO mice showed a marked increase in voluntary alcohol consumption without significant differences in preference for saccharin or aversion to quinine. These animals also exhibited higher conditioned place preference scores for alcohol than WT mice. Meanwhile, KO mice showed reduced sensitivity to alcohol and increased blood alcohol clearance. Furthermore, after the free consumption of alcohol, the activities of protein kinase B and glycogen synthase kinase 3β (GSK3β) increased in the dorsal striatum of WT mice, but not in KO mice, which showed high basal activity of Akt in the dorsal striatum. These results suggest that β-arrestin-2 negatively regulates alcohol preference and reward, likely through regulating the activation of signaling pathways including Akt/GSK3β in the dorsal striatum.

Keywords: β-arrestin, alcohol preference, Akt

Footnotes

These authors contributed equally to this work.

References

  • [1].Moonat S, Starkman BG, Sakharkar A, Pandey SC. Neuroscience of alcoholism: molecular and cellular mechanisms. Cell Mol Life Sci. 2010;67:73–88. doi: 10.1007/s00018-009-0135-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].Leshner AI. Addiction is a brain disease, and it matters. Science. 1997;278:45–47. doi: 10.1126/science.278.5335.45. [DOI] [PubMed] [Google Scholar]
  • [3].Robbins TW, Everitt BJ. Drug addiction: bad habits add up. Nature. 1999;398:567–570. doi: 10.1038/19208. [DOI] [PubMed] [Google Scholar]
  • [4].Mailliard WS, Diamond I. Recent advances in the neurobiology of alcoholism: the role of adenosine. Pharmacol Ther. 2004;101:39–46. doi: 10.1016/j.pharmthera.2003.10.002. [DOI] [PubMed] [Google Scholar]
  • [5].Ding ZM, Rodd ZA, Engleman EA, McBride WJ. Sensitization of ventral tegmental area dopamine neurons to the stimulating effects of ethanol. Alcohol Clin Exp Res. 2009;33:1571–1581. doi: 10.1111/j.1530-0277.2009.00985.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Thanos PK, Volkow ND, Freimuth P, Umegaki H, Ikari H, Roth G, et al. Overexpression of dopamine D2 receptors reduces alcohol self-administration. J Neurochem. 2001;78:1094–1103. doi: 10.1046/j.1471-4159.2001.00492.x. [DOI] [PubMed] [Google Scholar]
  • [7].Heidbreder CA, Andreoli M, Marcon C, Hutcheson DM, Gardner EL, Ashby CR., Jr. Evidence for the role of dopamine D3 receptors in oral operant alcohol self-administration and reinstatement of alcohol-seeking behavior in mice. Addict Biol. 2007;12:35–50. doi: 10.1111/j.1369-1600.2007.00051.x. [DOI] [PubMed] [Google Scholar]
  • [8].Yao L, Arolfo MP, Dohrman DP, Jiang Z, Fan P, Fuchs S, et al. betagamma Dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signaling and regulate ethanol consumption. Cell. 2002;109:733–743. doi: 10.1016/S0092-8674(02)00763-8. [DOI] [PubMed] [Google Scholar]
  • [9].Micioni Di Bonaventura MV, Cifani C, Lambertucci C, Volpini R, Cristalli G, Froldi R, et al. Effects of A(2)A adenosine receptor blockade or stimulation on alcohol intake in alcoholpreferring rats. Psychopharmacology (Berl) 2012;219:945–957. doi: 10.1007/s00213-011-2430-1. [DOI] [PubMed] [Google Scholar]
  • [10].Backstrom P, Bachteler D, Koch S, Hyytia P, Spanagel R. mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior. Neuropsychopharmacology. 2004;29:921–928. doi: 10.1038/sj.npp.1300381. [DOI] [PubMed] [Google Scholar]
  • [11].Hungund BL, Basavarajappa BS. Role of endocannabinoids and cannabinoid CB1 receptors in alcohol-related behaviors. Ann N Y Acad Sci. 2004;1025:515–527. doi: 10.1196/annals.1316.064. [DOI] [PubMed] [Google Scholar]
  • [12].Attramadal H, Arriza JL, Aoki C, Dawson TM, Codina J, Kwatra MM, et al. Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene family. J Biol Chem. 1992;267:17882–17890. [PubMed] [Google Scholar]
  • [13].Gurevich EV, Benovic JL, Gurevich VV. Arrestin2 and arrestin3 are differentially expressed in the rat brain during postnatal development. Neuroscience. 2002;109:421–436. doi: 10.1016/S0306-4522(01)00511-5. [DOI] [PubMed] [Google Scholar]
  • [14].DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK. Beta-arrestins and cell signaling. Annu Rev Physiol. 2007;69:483–510. doi: 10.1146/annurev.physiol.69.022405.154749. [DOI] [PubMed] [Google Scholar]
  • [15].Ma L, Pei G. Beta-arrestin signaling and regulation of transcription. J Cell Sci. 2007;120:213–218. doi: 10.1242/jcs.03338. [DOI] [PubMed] [Google Scholar]
  • [16].Fan XL, Zhang JS, Zhang XQ, Ma L. Chronic morphine treatment and withdrawal induce up-regulation of c-Jun N-terminal kinase 3 gene expression in rat brain. Neuroscience. 2003;122:997–1002. doi: 10.1016/j.neuroscience.2003.08.062. [DOI] [PubMed] [Google Scholar]
  • [17].Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature. 2000;408:720–723. doi: 10.1038/35047086. [DOI] [PubMed] [Google Scholar]
  • [18].Bohn LM, Lefkowitz RJ, Caron MG. Differential mechanisms of morphine antinociceptive tolerance revealed in (beta) arrestin-2 knock-out mice. J Neurosci. 2002;22:10494–10500. doi: 10.1523/JNEUROSCI.22-23-10494.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science. 1999;286:2495–2498. doi: 10.1126/science.286.5449.2495. [DOI] [PubMed] [Google Scholar]
  • [20].Bohn LM, Gainetdinov RR, Sotnikova TD, Medvedev IO, Lefkowitz RJ, Dykstra LA, et al. Enhanced rewarding properties of morphine, but not cocaine, in beta(arrestin)-2 knock-out mice. J Neurosci. 2003;23:10265–10273. doi: 10.1523/JNEUROSCI.23-32-10265.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Lefkowitz RJ, Rajagopal K, Whalen EJ. New roles for betaarrestins in cell signaling: not just for seven-transmembrane receptors. Mol Cell. 2006;24:643–652. doi: 10.1016/j.molcel.2006.11.007. [DOI] [PubMed] [Google Scholar]
  • [22].Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG. An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell. 2005;122:261–273. doi: 10.1016/j.cell.2005.05.012. [DOI] [PubMed] [Google Scholar]
  • [23].Urs NM, Daigle TL, Caron MG. A dopamine D1 receptordependent beta-arrestin signaling complex potentially regulates morphine-induced psychomotor activation but not reward in mice. Neuropsychopharmacology. 2011;36:551–558. doi: 10.1038/npp.2010.186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Bjork K, Rimondini R, Hansson AC, Terasmaa A, Hyytia P, Heilig M, et al. Modulation of voluntary ethanol consumption by beta-arrestin 2. FASEB J. 2008;22:2552–2560. doi: 10.1096/fj.07-102442. [DOI] [PubMed] [Google Scholar]
  • [25].George DT, Gilman J, Hersh J, Thorsell A, Herion D, Geyer C, et al. Neurokinin 1 receptor antagonism as a possible therapy for alcoholism. Science. 2008;319:1536–1539. doi: 10.1126/science.1153813. [DOI] [PubMed] [Google Scholar]
  • [26].Hodge CW, Mehmert KK, Kelley SP, McMahon T, Haywood A, Olive MF, et al. Supersensitivity to allosteric GABA(A) receptor modulators and alcohol in mice lacking PKCepsilon. Nat Neurosci. 1999;2:997–1002. doi: 10.1038/14795. [DOI] [PubMed] [Google Scholar]
  • [27].McGough NN, He DY, Logrip ML, Jeanblanc J, Phamluong K, Luong K, et al. RACK1 and brain-derived neurotrophic factor: a homeostatic pathway that regulates alcohol addiction. J Neurosci. 2004;24:10542–10552. doi: 10.1523/JNEUROSCI.3714-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Choi DS, Cascini MG, Mailliard W, Young H, Paredes P, McMahon T, et al. The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nat Neurosci. 2004;7:855–861. doi: 10.1038/nn1288. [DOI] [PubMed] [Google Scholar]
  • [29].Cunningham CL, Henderson CM, Bormann NM. Extinction of ethanol-induced conditioned place preference and conditioned place aversion: effects of naloxone. Psychopharmacology (Berl) 1998;139:62–70. doi: 10.1007/s002130050690. [DOI] [PubMed] [Google Scholar]
  • [30].Cunningham CL, Ferree NK, Howard MA. Apparatus bias and place conditioning with ethanol in mice. Psychopharmacology (Berl) 2003;170:409–422. doi: 10.1007/s00213-003-1559-y. [DOI] [PubMed] [Google Scholar]
  • [31].Oneda B, Preisig M, Dobrinas M, Eap CB. Lack of association between genetic polymorphisms of ARRB2 and alcohol dependence in a Caucasian population. Alcohol Alcohol. 2010;45:590–591. doi: 10.1093/alcalc/agq064. [DOI] [PubMed] [Google Scholar]
  • [32].Schuckit MA, Smith TL, Trim RS, Kuperman S, Kramer J, Hesselbrock V, et al. Sex differences in how a low sensitivity to alcohol relates to later heavy drinking. Drug Alcohol Rev. 2012;317:871–880. doi: 10.1111/j.1465-3362.2012.00469.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Schuckit MA, Smith TL, Anderson KG, Brown SA. Testing the level of response to alcohol: social information processing model of alcoholism risk—a 20-year prospective study. Alcohol Clin Exp Res. 2004;28:1881–1889. doi: 10.1097/01.ALC.0000148111.43332.A5. [DOI] [PubMed] [Google Scholar]
  • [34].Beaulieu JM, Marion S, Rodriguiz RM, Medvedev IO, Sotnikova TD, Ghisi V, et al. A beta-arrestin 2 signaling complex mediates lithium action on behavior. Cell. 2008;132:125–136. doi: 10.1016/j.cell.2007.11.041. [DOI] [PubMed] [Google Scholar]
  • [35].Neasta J, Ben Hamida S, Yowell QV, Carnicella S, Ron D. AKT signaling pathway in the nucleus accumbens mediates excessive alcohol drinking behaviors. Biol Psychiatry. 2011;70:575–582. doi: 10.1016/j.biopsych.2011.03.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Bjork K, Terasmaa A, Sun H, Thorsell A, Sommer WH, Heilig M. Ethanol-induced activation of AKT and DARPP-32 in the mouse striatum mediated by opioid receptors. Addict Biol. 2010;15:299–303. doi: 10.1111/j.1369-1600.2010.00212.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES