Skip to main content
SpringerLink
Log in

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

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

An Erratum to this article was published on 21 September 2016

Abstract

Rationale

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.

Methods

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.

Results

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.

Conclusion

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

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Antal-Zimanyi I, Khawaja X (2009) The role of melanin-concentrating hormone in energy homeostasis and mood disorders. J Mol Neurosci 39:86–98

    Article  CAS  PubMed  Google Scholar 

  • 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 319:218–245

    Article  CAS  PubMed  Google Scholar 

  • 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 15:299–303

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 143:2469–2477

    Article  CAS  PubMed  Google Scholar 

  • 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 106:6772–6777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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) 211:367–375

    Article  CAS  Google Scholar 

  • 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 47:227–241

    Article  PubMed  Google Scholar 

  • 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 29:310–316

    Article  CAS  PubMed  Google Scholar 

  • 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 85:728–735

    Article  CAS  PubMed  Google Scholar 

  • 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 31:1325–1337

    Article  CAS  PubMed  Google Scholar 

  • 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 329:429–438

    Article  CAS  PubMed  Google Scholar 

  • 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 25:2933–2940

    Article  CAS  PubMed  Google Scholar 

  • Gould TD, Manji HK (2005) DARPP-32: a molecular switch at the nexus of reward pathway plasticity. Proc Natl Acad Sci U S A 102:253–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 141:4524–4532

    Article  CAS  PubMed  Google Scholar 

  • 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 12:1194–1216

  • 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 30:339–349

    Article  Google Scholar 

  • 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 102:400–406

    Article  CAS  PubMed  Google Scholar 

  • 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 25:1361–1373

    Article  PubMed  Google Scholar 

  • 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 99:3240–3245

  • Nestler EJ (2002) Common molecular and cellular substrates of addiction and memory. Neurobiol Learn Mem 78:637–647

    Article  CAS  PubMed  Google Scholar 

  • Nishi A, Snyder GL, Greengard P (1997) Bidirectional regulation of DARPP-32 phosphorylation by dopamine. J Neurosci 17:8147–8155

    CAS  PubMed  Google Scholar 

  • Nishi A, Kuroiwa M, Shuto T (2011) Mechanisms for the modulation of dopamine D1 receptor signaling in striatal neurons. Front Neuroanat 5:43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates: hard cover edition. Academic Press, Cambridge, MA, USA

  • Phillipson O, Griffiths A (1985) The topographic order of inputs to nucleus accumbens in the rat. Neuroscience 16:275–296

    Article  CAS  PubMed  Google Scholar 

  • 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 27:606–620

    Article  CAS  PubMed  Google Scholar 

  • 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 64:184–191

    Article  CAS  PubMed  Google Scholar 

  • 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:e47934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 67:17–24

    Article  CAS  PubMed  Google Scholar 

  • Risinger FO, Freeman PA, Greengard P, Fienberg AA (2001) Motivational effects of ethanol in DARPP-32 knock-out mice. J Neurosci 21:340–348

    CAS  PubMed  Google Scholar 

  • 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 30:8263–8273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 36:3126–3133

    Article  PubMed  Google Scholar 

  • 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 31:1135–1145

    Google Scholar 

  • 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 25:914–922

    Article  CAS  PubMed  Google Scholar 

  • 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 19:11040–11048

    CAS  PubMed  Google Scholar 

  • Svenningsson P, Nairn AC, Greengard P (2005) DARPP-32 mediates the actions of multiple drugs of abuse. AAPS J 7:E353–E360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 79:785–792

  • 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) 209:103–111

    Article  CAS  Google Scholar 

  • 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 33:10132–10142

  • Tzschentke TM (2007) Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 12:227–462

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, Linkopings University, Linkoping, Sweden

    Camilla Karlsson, Alison L. Atkins, Annika Thorsell & Markus Heilig

  2. Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA

    Faazal Rehman & Ruslan Damdazic

  3. Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA

    Jesse R. Schank

  4. Neuroscience and Endocrine Discovery Research, Lilly Research Laboratories, a Division of Eli Lilly and Company, Indianapolis, IN, USA

    Donald R. Gehlert

  5. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Pia Steensland

Authors
  1. Camilla Karlsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Faazal Rehman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruslan Damdazic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alison L. Atkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jesse R. Schank
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Donald R. Gehlert
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pia Steensland
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Annika Thorsell
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Markus Heilig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Markus Heilig.

Ethics declarations

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.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00213-016-4434-3.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 106 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Karlsson, C., Rehman, F., Damdazic, R. et al. The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation. Psychopharmacology 233, 2355–2363 (2016). https://doi.org/10.1007/s00213-016-4285-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-016-4285-y

Keywords

Search

Navigation