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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 and Ralph J. DiLeone^1,2

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

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Received May 4, 2004; revised February 6, 2005; accepted February 11, 2005.

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