The Hypothalamic Neuropeptide Melanin-Concentrating Hormone Acts in the Nucleus Accumbens to Modulate Feeding Behavior and Forced-Swim Performance

• Published in: The Journal of neuroscience 2005-03, Vol.25 (11), p.2933-2940
• Main Authors: Georgescu, Dan, Sears, Robert M, Hommel, Jonathan D, Barrot, Michel, Bolanos, Carlos A, Marsh, Donald J, Bednarek, Maria A, Bibb, James A, Maratos-Flier, Eleftheria, Nestler, Eric J, DiLeone, Ralph J
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Behavior, Animal; Behavioral/Systems/Cognitive; Benzazepines - pharmacology; Blotting, Western - methods; Cyclic AMP Response Element-Binding Protein - genetics; Dopamine Agonists - pharmacology; Dose-Response Relationship, Drug; Drug Interactions; Dynorphins - genetics; Dynorphins - metabolism; Eating - drug effects; Enkephalins - genetics; Enkephalins - metabolism; Feeding Behavior - drug effects; Feeding Behavior - physiology; Food Deprivation - physiology; Gene Expression Regulation - drug effects; Hypothalamic Hormones - deficiency; Hypothalamic Hormones - pharmacology; Immunohistochemistry - methods; In Situ Hybridization, Fluorescence - methods; Intracellular Signaling Peptides and Proteins - metabolism; Life Sciences; Melanins - deficiency; Melanins - pharmacology; Mice; Mice, Transgenic; Neurons - metabolism; Neurons and Cognition; Neuropeptides - metabolism; Nucleus Accumbens - cytology; Nucleus Accumbens - drug effects; Nucleus Accumbens - physiology; Orexin Receptors; Orexins; Pituitary Hormones - deficiency; Pituitary Hormones - pharmacology; Rats; Rats, Sprague-Dawley; Reaction Time - drug effects; Reaction Time - genetics; Receptors, AMPA - metabolism; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Receptors, Pituitary Hormone - antagonists & inhibitors; Receptors, Pituitary Hormone - metabolism; Serine - metabolism; Swimming - physiology; Time Factors
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1714-04.2005

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide with a prominent role in feeding and energy homeostasis. The rodent MCH receptor (MCH1R) is highly expressed in the nucleus accumbens shell (AcSh), a region that is important in the regulation of appetitive behavior. Here we establish a role for MCH and MCH1R in mediating a hypothalamic-limbic circuit that regulates feeding and related behaviors. Direct delivery of an MCH1R receptor antagonist to the AcSh blocked feeding and produced an antidepressant-like effect in the forced swim test, whereas intra-AcSh injection of MCH had the opposite effect. Expression studies demonstrated that MCH1R is present in both the enkephalin- and dynorphin-positive medium spiny neurons of the AcSh. Biochemical analysis in AcSh explants showed that MCH signaling blocks dopamine-induced phosphorylation of the AMPA glutamate receptor subunit GluR1 at Ser845. Finally, food deprivation, but not other stressors, stimulated cAMP response element-binding protein-dependent pathways selectively in MCH neurons of the hypothalamus, suggesting that these neurons are responsive to a specific set of physiologically relevant conditions. This work identifies a novel hypothalamic-AcSh circuit that influences appetitive behavior and mediates the antidepressant activity of MCH1R antagonists.