Abstract
Rationale
Melanin-concentrating hormone (MCH) is involved in regulation of appetitive behaviors as well as emotional reactivity and reward, behavioral domains relevant to alcohol addiction.
Materials and methods
We evaluated the effects of the non-peptide MCH1 receptor antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one; 3–30 mg/kg, i.p.] on alcohol-related behaviors in Wistar rats.
Results
Ex vivo binding experiments demonstrated that the GW803430 dose range used resulted in high central MCH1 receptor occupancy. Alcohol self-administration was dose-dependently and potently suppressed, by approximately 80% at the highest dose. Reinstatement of alcohol-seeking induced by alcohol-associated cues was essentially eliminated. In contrast, reinstatement induced by footshock stress was not significantly altered. Taste preference for a quinine/saccharin solution, locomotor activity, and alcohol elimination were unaffected.
Conclusion
Together, these observations support a specific involvement of the MCH system in mediating alcohol reward and cue-induced relapse to alcohol seeking. MCH1-R antagonism may constitute an attractive treatment target for alcohol use disorders.
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References
Bednarek MA, Hreniuk DL, Tan C, Palyha OC, MacNeil DJ, Van der Ploeg LHY, Howard AD, Feighner SD (2002) Synthesis and biological evaluation in vitro of selective, high affinity peptide antagonists of human melanin-concentrating hormone action at human melanin-concentrating hormone receptor 1. Biochemistry (Mosc) 41:6383–6390
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
Borowsky B, Durkin MM, Ogozalek K, Marzabadi MR, DeLeon J, Lagu B, Heurich R, Lichtblau H, Shaposhnik Z, Daniewska I, Blackburn TP, Branchek TA, Gerald C, Vaysse PJ, Forray C (2002) Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nat Med 8:825–830
Bouza C, Angeles M, Munoz A, Amate JM (2004) Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 99:811–828
Catania AC (1992) Learning, 3rd edn. Prentice Hall, Englewood Cliffs
Chaki S, Hirota S, Funakoshi T, Suzuki Y, Suetake S, Okubo T, Ishii T, Nakazato A, Okuyama S (2003) Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-met hoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor. J Pharmacol Exp Ther 304:818–826
Chaki S, Yamaguchi J, Yamada H, Thomsen W, Tran TA, Semple G, Sekiguchi Y (2005) ATC0175: an orally active melanin-concentrating hormone receptor 1 antagonist for the potential treatment of depression and anxiety. CNS Drug Rev 11:341–352
Chen Y, Hu C, Hsu CK, 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
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 U S A 106:6772–6777
Cippitelli A, Bilbao A, Hansson AC, Del Arco I, Sommer W, Heilig M, Massi M, Bermudez-Silva FJ, Navarro M, Ciccocioppo R, De Fonseca FR, The European TARGALC Consortium (2005) Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol-seeking behavior in rats. Eur J Neurosci 21:2243–2251
Cippitelli A, Cannella N, Braconi S, Duranti A, Tontini A, Bilbao A, Defonseca FR, Piomelli D, Ciccocioppo R (2008) Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat. Psychopharmacology (Berl) 198:449–460
DiLeone RJ, Georgescu D, Nestler EJ (2003) Lateral hypothalamic neuropeptides in reward and drug addiction. Life Sci 73:759–768
Duncan EA, Proulx K, Woods SC (2005) Central administration of melanin-concentrating hormone increases alcohol and sucrose/quinine intake in rats. Alcohol Clin Exp Res 29:958–964
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
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
Gehlert DR, Rasmussen K, Shaw J, Li X, Ardayfio P, Craft L, Coskun T, Zhang HY, Chen YY, 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
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
Gilpin NW, Stewart RB, Elder RL, Kho Y, Murphy JM, Li TK, Badia-Elder NE (2004) Sedative and motor-impairing effects of neuropeptide Y and ethanol in selectively bred P and NP rats. Pharmacol Biochem Behav 78:65–73
Goodwin FL, Amit Z (1998) Do taste factors contribute to the mediation of ethanol intake? Ethanol and saccharin-quinine intake in three rat strains. Alcohol Clin Exp Res 22:837–844
Heilig M, Egli M (2006) Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharm Therap 111:855–876
Hertzog DL, Al-Barazanji KA, Bigharn EC, Bishop MJ, Britt CS, Carlton DL, Cooper JP, Daniels AJ, Garrido DM, Goetz AS, Grizzle MK, Guo YC, Handlon AL, Ignar DM, Morgan RO, Peat AJ, Tavares FX, Zhou HQ (2006) The discovery and optimization of pyrimidinone-containing MCH R1 antagonists. Bioorg Med Chem Lett 16:4723–4727
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
Kalivas PW, McFarland K (2003) Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology (Berl) 168:44–56
Kawauchi H, Kawazoe I, Tsubokawa M, Kishida M, Baker BI (1983) Characterization of melanin-concentrating hormone in Chum Salmon Pituitaries. Nature 305:321–323
Kowalski TJ, Sasikumar T (2007) Melanin-concentrating hormone receptor-1 antagonists as antiobesity therapeutics: current status. BioDrugs 21:311–321
Le AD, Harding S, Juzytsch W, Funk D, Shaham Y (2005) Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology (Berl) 179:366–373
Marsh DJ, Weingarth DT, Novi DE, Chen HY, Trumbauer ME, Chen AS, Guan XM, 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 U S A 99:3240–3245
Morens C, Norregaard P, Receveur JM, van Dijk G, Scheurink AJ (2005) Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake. Brain Res 1062:32–38
Nair SG, Adams-Deutsch T, Pickens CL, Smith DG, Shaham Y (2009) Effects of the MCH1 receptor antagonist SNAP 94847 on high-fat food-reinforced operant responding and reinstatement of food seeking in rats. Psychopharmacology (Berl) 205:129–140
Pissios P, Frank L, Kennedy AR, Porter DR, Marino FE, Liu FF, Pothos EN, Maratos-Flier E (2008) Dysregulation of the mesolimbic dopamine system and reward in MCH-/- mice. Biol Psychiatry 64:184–191
Rimondini R, Sommer WH, Dall’olio R, Heilig M (2008) Long-lasting tolerance to alcohol following a history of dependence. Addict Biol 13:26–30
Saito Y, Cheng M, Leslie FM, Civelli O (2001) Expression of the melanin-concentrating hormone (MCH) receptor mRNA in the rat brain. J Comp Neurol 435:26–40
Shaham Y, Shalev U, Lu L, de Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168:3–20
Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–42
Smith DG, Tzavara ET, Shaw J, Luecke S, Wade M, Davis R, Salhoff C, Nomikos GG, Gehlert DR (2005) Mesolimbic dopamine super-sensitivity in melanin-concentrating hormone-1 receptor-deficient mice. J Neurosci 25:914–922
Smith DG, Davis RJ, Rorick-Kehn L, Morin M, Witkin JM, McKinzie DL, Nomikos GG, Gehlert DR (2006) Melanin-concentrating hormone-1 receptor modulates neuroendocrine, behavioral, and corticolimbic neurochemical stress responses in mice. Neuropsychopharmacology 31:1135–1145
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
Weiss F, Lorang MT, Bloom FE, Koob GF (1993) Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants. J Pharmacol Exp Ther 267:250–258
Wise RA (2004) Dopamine, learning and motivation. Nat Rev Neurosci 5:483–494
Acknowledgements
We are thankful to Karen Smith for careful revision of the paper and Melige Monique for animal care.
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The authors declare no conflicts of interest.
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ESM Table 1
GW803430 did not exhibit activity below 100 nM as shown in a panel of common and non-common drug targets used to evaluate the MCH-1 receptor antagonism selectivity. (DOC 175 kb)
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Cippitelli, A., Karlsson, C., Shaw, J.L. et al. Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats. Psychopharmacology 211, 367–375 (2010). https://doi.org/10.1007/s00213-010-1891-y
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DOI: https://doi.org/10.1007/s00213-010-1891-y