Melanin-concentrating hormone (MCH) is a bioactive peptide found in 1980 as a modulator of skin coloration in fishes and amphibians. It had not attracted much attention in research until 1995, when it was shown to be induced in genetically obese mice and to be able to increase food intake when injected intracerebroventrically. This made the MCH system a target for anti-obesity drug design, an aim however not feasible for lack of knowledge of the MCH receptor. This changed with our and others discovery of the molecular structure of MCH1 receptor (MCH1R), which propelled the MCH system at the forefront of anti obesity drug research. Our study on the expression profile of the MCH1R however had led to the conclusion that there was much more to the MCH system than only a role in feeding behavior. Of most interest, we had found that the MCH system is predominantly a CNS system and that the highest level of MCH1R expression is in the shell of the nucleus accumbens. We therefore hypothesized that the MCH system may have a role in reward. First, we found that MCH1R KO mice exhibit a reduced cocaine-induced response in the conditioned place preference assay, an indication that the MCH system may regulate motivation for cocaine. This incited us to isolate a MCH1R antagonist to test the acute effects that blockade of the MCH system may have on reward responses. We found that blockade of the MCH system has no effect on food reward but has a profound effect on cocaine reinforcement and reinstatement. These results, although preliminary, point at the MCH system as a novel neuropeptide system involved in modulating drug of abuse related responses. Since reward is known to rely on the dopaminergic system extending from the ventrotegmental area to the nucleus accumbens, we hypothesize that the MCH system evokes its modulatory role by interacting with dopamine receptor positive cells in the shell of the nucleus accumbens and propose to analyze the role of the MCH system in reinforcing behaviors.

Public Health Relevance

If we can demonstrate that the MCH system can regulate the motivational aspect of drugs of abuse, we will have discovered a novel transmitter system involved in addiction. Since we may show that the MCH system may block drug relapse, our data may serve as a basis to use the MCH system as a possible target for helping fight drugs of abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA024746-03
Application #
8215754
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Frankenheim, Jerry
Project Start
2010-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$364,791
Indirect Cost
$108,228
Name
University of California Irvine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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Zhang, Li; Parks, Gregory S; Wang, Zhiwei et al. (2013) Anatomical characterization of bombesin receptor subtype-3 mRNA expression in the rodent central nervous system. J Comp Neurol 521:1020-39
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Zhang, Yan; Wang, Zhiwei; Parks, Gregory Scott et al. (2011) Novel neuropeptides as ligands of orphan G protein-coupled receptors. Curr Pharm Des 17:2626-31
Chung, Shinjae; Parks, Gregory S; Lee, Cheol et al. (2011) Recent updates on the melanin-concentrating hormone (MCH) and its receptor system: lessons from MCH1R antagonists. J Mol Neurosci 43:115-21

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