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The Journal of Neuroscience, March 16, 2005, 25(11):2933-2940; doi:10.1523/JNEUROSCI.1714-04.2005
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Behavioral/Systems/Cognitive
The Hypothalamic Neuropeptide Melanin-Concentrating Hormone Acts in the Nucleus Accumbens to Modulate Feeding Behavior and Forced-Swim Performance
Dan Georgescu,1 Robert M. Sears,1,2 Jonathan D. Hommel,1 Michel Barrot,1 Carlos A. Bolaños,3 Donald J. Marsh,4 Maria A. Bednarek,5 James A. Bibb,1 Eleftheria Maratos-Flier,6 Eric J. Nestler,1 andRalph J. DiLeone1,2 1Department of Psychiatry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9070, 2Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, 3Departments of Psychology and Neuroscience, Florida State University, Tallahassee, Florida 32306, Departments of 4Metabolic Disorders and 5Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, and 6Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215
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.
Key words: feeding; MCH; accumbens; lateral hypothalamus; neuropeptide; obesity; depression; appetite
Received May 4, 2004; revised February 6, 2005; accepted February 11, 2005.
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