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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Frankenheim, Jerry
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Schools of Medicine
United States
Zip Code
Zhang, Yan; Liu, Yanfang; Wu, Lehao et al. (2018) Receptor-specific crosstalk between prostanoid E receptor 3 and bombesin receptor subtype 3. FASEB J 32:3184-3192
Sanathara, Nayna M; Garau, Celia; Alachkar, Amal et al. (2018) Melanin concentrating hormone modulates oxytocin-mediated marble burying. Neuropharmacology 128:22-32
Alachkar, Amal; Alhassen, Lamees; Wang, Zhiwei et al. (2016) Inactivation of the melanin concentrating hormone system impairs maternal behavior. Eur Neuropsychopharmacol 26:1826-1835
Wang, Lien; Alachkar, Amal; Sanathara, Nayna et al. (2015) A Methionine-Induced Animal Model of Schizophrenia: Face and Predictive Validity. Int J Neuropsychopharmacol 18:
Long, Zhen; Zhang, Yan; Guo, Zhimou et al. (2014) Amide alkaloids from Scopolia tangutica. Planta Med 80:1124-30
Zhang, Yan; Wang, Chaoran; Guo, Zhimou et al. (2014) Discovery of N-methyltetrahydroprotoberberines with ?-opioid receptor agonists-opioid receptor agonist activities from corydalis yanhusuo W. T. Wang by using two-dimensional liquid chromatography. J Ethnopharmacol 155:1597-602
Zhang, Yan; Wang, Chaoran; Wang, Lien et al. (2014) A novel analgesic isolated from a traditional Chinese medicine. Curr Biol 24:117-23
Parks, Gregory S; Wang, Lien; Wang, Zhiwei et al. (2014) Identification of neuropeptide receptors expressed by melanin-concentrating hormone neurons. J Comp Neurol 522:3817-33
Parks, Gregory S; Olivas, Nicholas D; Ikrar, Taruna et al. (2014) Histamine inhibits the melanin-concentrating hormone system: implications for sleep and arousal. J Physiol 592:2183-96
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

Showing the most recent 10 out of 23 publications