, Volume 233, Issue 12, pp 2355–2363 | Cite as

The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation

  • Camilla Karlsson
  • Faazal Rehman
  • Ruslan Damdazic
  • Alison L. Atkins
  • Jesse R. Schank
  • Donald R. Gehlert
  • Pia Steensland
  • Annika Thorsell
  • Markus Heilig
Original Investigation



Melanin-concentrating hormone (MCH) is involved in the regulation of food intake and has recently been associated with alcohol-related behaviors. Blockade of MCH-1 receptors (MCH1-Rs) attenuates operant alcohol self-administration and decreases cue-induced reinstatement, but the mechanism through which the MCH1-R influences these behaviors remains unknown. MCH1-Rs are highly expressed in the nucleus accumbens shell (NAcSh) where they are co-expressed with dopamine (DA) receptors. MCH has been shown to potentiate responses to dopamine and to increase phosphorylation of DARPP-32, an intracellular marker of DA receptor activation, in the NAcSh.


In the present study, we investigated the role of the MCH1-R in alcohol reward using the conditioned place preference (CPP) paradigm. We then used immunohistochemistry (IHC) to assess activation of downstream signaling after administration of a rewarding dose of alcohol.


We found that alcohol-induced CPP was markedly decreased in mice with a genetic deletion of the MCH1-R as well as after pharmacological treatment with an MCH1-R antagonist, GW803430. In contrast, an isocaloric dose of dextrose did not produce CPP. The increase in DARPP-32 phosphorylation seen in wildtype (WT) mice after acute alcohol administration in the NAcSh was markedly reduced in MCH1-R knock-out (KO) mice.


Our results suggest that MCH1-Rs regulate the rewarding properties of alcohol through interactions with signaling cascades downstream of DA receptors in the NAcSh.


Alcohol Conditioned place preference (CPP) Knock-out mice MCH1-R p-DARPP-32 Reward 


Compliance with ethical standards

All experiments were conducted during the light cycle and performed according to the National Institutes of Health Guidelines for Care and Use of Laboratory Animals and approved by the NIAAA ACUC.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

213_2016_4285_MOESM1_ESM.docx (107 kb)
ESM 1 (DOCX 106 kb)


  1. Antal-Zimanyi I, Khawaja X (2009) The role of melanin-concentrating hormone in energy homeostasis and mood disorders. J Mol Neurosci 39:86–98CrossRefPubMedGoogle Scholar
  2. Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon JL, Vale W, Sawchenko PE (1992) The melanin-concentrating hormone system of the rat brain: an immuno-and hybridization histochemical characterization. J Comp Neurol 319:218–245CrossRefPubMedGoogle Scholar
  3. Björk K, Terasmaa A, Sun H, Thorsell A, Sommer WH, Heilig M (2010) Ethanol‐induced activation of AKT and DARPP‐32 in the mouse striatum mediated by opioid receptors. Addict Biol 15:299–303CrossRefPubMedPubMedCentralGoogle Scholar
  4. Chen Y, Hu C, Hsu C-K, Zhang Q, Bi C, Asnicar M, Hsiung HM, Fox N, Slieker LJ, Yang DD, Heiman ML, Shi Y (2002) Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology 143:2469–2477CrossRefPubMedGoogle Scholar
  5. Chung S, Hopf FW, Nagasaki H, Li CY, Belluzzi JD, Bonci A, Civelli O (2009) The melanin-concentrating hormone system modulates cocaine reward. Proc Natl Acad Sci USA 106:6772–6777CrossRefPubMedPubMedCentralGoogle Scholar
  6. Cippitelli A, Karlsson C, Shaw JL, Thorsell A, Gehlert DR, Heilig M (2010) Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats. Psychopharmacology (Berl) 211:367–375CrossRefGoogle Scholar
  7. Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D (2004) Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47:227–241CrossRefPubMedGoogle Scholar
  8. Donohue T, Hoffman PL, Tabakoff B (2005) Effect of ethanol on DARPP‐32 phosphorylation in transgenic mice that express human type VII adenylyl cyclase in brain. Alcohol Clin Exp Res 29:310–316CrossRefPubMedGoogle Scholar
  9. Duncan EA, Rider TR, Jandacek RJ, Clegg DJ, Benoit SC, Tso P, Woods SC (2006) The regulation of alcohol intake by melanin-concentrating hormone in rats. Pharmacol Biochem Behav 85:728–735CrossRefPubMedGoogle Scholar
  10. Duncan EA, Sorrell JE, Adamantidis A, Rider T, Jandacek RJ, Seeley RJ, Lakaye B, Woods SC (2007) Alcohol drinking in MCH receptor-1-deficient mice. Alcohol Clin Exp Res 31:1325–1337CrossRefPubMedGoogle Scholar
  11. Gehlert DR, Rasmussen K, Shaw J, Li X, Ardayfio P, Craft L, Coskun T, Zhang HY, Chen Y, Witkin JM (2009) Preclinical evaluation of melanin-concentrating hormone receptor 1 antagonism for the treatment of obesity and depression. J Pharmacol Exp Ther 329:429–438CrossRefPubMedGoogle Scholar
  12. Georgescu D, Sears RM, Hommel JD, Barrot M, Bolanos CA, Marsh DJ, Bednarek MA, Bibb JA, Maratos-Flier E, Nestler EJ, DiLeone RJ (2005) The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. J Neurosci 25:2933–2940CrossRefPubMedGoogle Scholar
  13. Gould TD, Manji HK (2005) DARPP-32: a molecular switch at the nexus of reward pathway plasticity. Proc Natl Acad Sci U S A 102:253–254CrossRefPubMedPubMedCentralGoogle Scholar
  14. Hawes BE, Kil E, Green B, O’Neill K, Fried S, Graziano MP (2000) The melanin-concentrating hormone receptor couples to multiple G proteins to activate diverse intracellular signaling pathways. Endocrinology 141:4524–4532CrossRefPubMedGoogle Scholar
  15. Hervieu GJ, Cluderay JE, Harrison D, Meakin J, Maycox P, Nasir S, Leslie RA (2000) The distribution of the mRNA and protein products of the melanin‐concentrating hormone (MCH) receptor gene, slc‐1, in the central nervous system of the rat. Eur J Neurosci 12:1194–1216Google Scholar
  16. Houchi H, Babovic D, Pierrefiche O, Ledent C, Daoust M, Naassila M (2004) CB1 receptor knockout mice display reduced ethanol-induced conditioned place preference and increased striatal dopamine D2 receptors. Neuropsychopharmacology 30:339–349CrossRefGoogle Scholar
  17. Karlsson C, Zook M, Ciccocioppo R, Gehlert DR, Thorsell A, Heilig M, Cippitelli A (2012) Melanin-concentrating hormone receptor 1 (MCH1-R) antagonism: reduced appetite for calories and suppression of addictive-like behaviors. Pharmacol Biochem Behav 102:400–406CrossRefPubMedGoogle Scholar
  18. Le Barillier L, Léger L, Luppi PH, Fort P, Malleret G, Salin PA (2015) Genetic deletion of melanin‐concentrating hormone neurons impairs hippocampal short‐term synaptic plasticity and hippocampal‐dependent forms of short‐term memory. Hippocampus 25:1361–1373CrossRefPubMedGoogle Scholar
  19. Marsh DJ, Weingarth DT, Novi DE, Chen HY, Trumbauer ME, Chen AS, Guan X-M, Jiang MM, Feng Y, Camacho RE, Shen Z, Frazier EG, Yu H, Metzger JM, Kuca SJ, Shearman LP, Gopal-Truter S, MacNeil DJ,Strack AM, MacIntyre DE, Van der Ploeg LH, Qian S (2002) Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci USA 99:3240–3245Google Scholar
  20. Nestler EJ (2002) Common molecular and cellular substrates of addiction and memory. Neurobiol Learn Mem 78:637–647CrossRefPubMedGoogle Scholar
  21. Nishi A, Snyder GL, Greengard P (1997) Bidirectional regulation of DARPP-32 phosphorylation by dopamine. J Neurosci 17:8147–8155PubMedGoogle Scholar
  22. Nishi A, Kuroiwa M, Shuto T (2011) Mechanisms for the modulation of dopamine D1 receptor signaling in striatal neurons. Front Neuroanat 5:43CrossRefPubMedPubMedCentralGoogle Scholar
  23. Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates: hard cover edition. Academic Press, Cambridge, MA, USAGoogle Scholar
  24. Phillipson O, Griffiths A (1985) The topographic order of inputs to nucleus accumbens in the rat. Neuroscience 16:275–296CrossRefPubMedGoogle Scholar
  25. Pissios P, Bradley RL, Maratos-Flier E (2006) Expanding the scales: The multiple roles of MCH in regulating energy balance and other biological functions. Endocr Rev 27:606–620CrossRefPubMedGoogle Scholar
  26. Pissios P, Frank L, Kennedy AR, Porter DR, Marino FE, Liu F-F, Pothos EN, Maratos-Flier E (2008) Dysregulation of the mesolimbic dopamine system and reward in MCH−/− mice. Biol Psychiatry 64:184–191CrossRefPubMedGoogle Scholar
  27. Randall PA, Pardo M, Nunes EJ, López Cruz L, Vemuri VK, Makriyannis A, Baqi Y, Müller CE, Correa M, Salamone JD (2012) Dopaminergic modulation of effort-related choice behavior as assessed by a progressive ratio chow feeding choice task: pharmacological studies and the role of individual differences. PLoS One 7:e47934CrossRefPubMedPubMedCentralGoogle Scholar
  28. Risinger FO, Cunningham CL (2000) DBA/2J mice develop stronger lithium chloride-induced conditioned taste and place aversions than C57BL/6J mice. Pharmacol Biochem Behav 67:17–24CrossRefPubMedGoogle Scholar
  29. Risinger FO, Freeman PA, Greengard P, Fienberg AA (2001) Motivational effects of ethanol in DARPP-32 knock-out mice. J Neurosci 21:340–348PubMedGoogle Scholar
  30. Sears RM, Liu R-J, Narayanan NS, Sharf R, Yeckel MF, Laubach M, Aghajanian GK, DiLeone RJ (2010) Regulation of nucleus accumbens activity by the hypothalamic neuropeptide melanin-concentrating hormone. J Neurosci 30:8263–8273CrossRefPubMedPubMedCentralGoogle Scholar
  31. Sherwood A, Wosiski‐Kuhn M, Nguyen T, Holland PC, Lakaye B, Adamantidis A, Johnson AW (2012) The role of melanin‐concentrating hormone in conditioned reward learning. Eur J Neurosci 36:3126–3133CrossRefPubMedGoogle Scholar
  32. Smith DG, Davis RJ, Rorick-Kehn L, Morin M, Witkin JM, McKinzie DL, Nomikos GG, Gehlert DR (2005a) Melanin-concentrating hormone-1 receptor modulates neuroendocrine, behavioral, and corticolimbic neurochemical stress responses in mice. Neuropsychopharmacology 31:1135–1145Google Scholar
  33. Smith DG, Tzavara ET, Shaw J, Luecke S, Wade M, Davis R, Salhoff C, Nomikos GG, Gehlert DR (2005b) Mesolimbic dopamine super-sensitivity in melanin-concentrating hormone-1 receptor-deficient mice. J Neurosci 25:914–922CrossRefPubMedGoogle Scholar
  34. Stratford TR, Kelley AE (1999) Evidence of a functional relationship between the nucleus accumbens shell and lateral hypothalamus subserving the control of feeding behavior. J Neurosci 19:11040–11048PubMedGoogle Scholar
  35. Svenningsson P, Nairn AC, Greengard P (2005) DARPP-32 mediates the actions of multiple drugs of abuse. AAPS J 7:E353–E360CrossRefPubMedPubMedCentralGoogle Scholar
  36. Tan CP, Sano H, Iwaasa H, Pan J, Sailer AW, Hreniuk DL, Feighner SD, Palyha OC, Pong SS, Figueroa DJ, Austin CP, Jiang MM, Yu H, Ito J, Ito M, Ito M, Guan XM, MacNeil DJ, Kanatani A,Van der Ploeg LH, Howard AD (2002) Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression. Genomics 79:785–792Google Scholar
  37. Thorsell A, Schank JR, Singley E, Hunt SP, Heilig M (2010) Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice. Psychopharmacology (Berl) 209:103–111CrossRefGoogle Scholar
  38. Thorsell A, Tapocik JD, Liu K, Zook M, Bell L, Flanigan M, Patnaik S, Marugan J, Damadzic R, Dehdashti SJ, Schwandt ML, Southall N, Austin CP, Eskay R, Ciccocioppo R, Zheng W, Heilig M (2013) A novel brain penetrant NPS receptor antagonist, NCGC00185684, blocks alcohol-induced ERK-phosphorylation in the central amygdala and decreases operant alcohol self-administration in rats. J Neurosci 33:10132–10142Google Scholar
  39. Tzschentke TM (2007) Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 12:227–462CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Camilla Karlsson
    • 1
  • Faazal Rehman
    • 2
  • Ruslan Damdazic
    • 2
  • Alison L. Atkins
    • 1
  • Jesse R. Schank
    • 3
  • Donald R. Gehlert
    • 4
  • Pia Steensland
    • 5
  • Annika Thorsell
    • 1
  • Markus Heilig
    • 1
  1. 1.Department of Clinical and Experimental MedicineLinkopings UniversityLinkopingSweden
  2. 2.Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA)National Institutes of Health (NIH)BethesdaUSA
  3. 3.Department of Physiology and PharmacologyUniversity of GeorgiaAthensUSA
  4. 4.Neuroscience and Endocrine Discovery Research, Lilly Research Laboratories, a Division of Eli Lilly and CompanyIndianapolisUSA
  5. 5.Department of Clinical NeuroscienceKarolinska InstitutetStockholmSweden

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