The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation
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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.
KeywordsAlcohol 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.
- 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
- 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
- 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
- Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates: hard cover edition. Academic Press, Cambridge, MA, USAGoogle 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:e47934CrossRefPubMedPubMedCentralGoogle 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 31:1135–1145Google 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 79:785–792Google 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 33:10132–10142Google Scholar