Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Analysis of Variance
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Animals
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Behavior, Animal
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Benzazepines / pharmacology
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Blotting, Western / methods
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Cyclic AMP Response Element-Binding Protein / genetics
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Dopamine Agonists / pharmacology
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Dose-Response Relationship, Drug
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Drug Interactions
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Dynorphins / genetics
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Dynorphins / metabolism
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Eating / drug effects
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Enkephalins / genetics
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Enkephalins / metabolism
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Feeding Behavior / drug effects*
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Feeding Behavior / physiology
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Food Deprivation / physiology
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Gene Expression Regulation / drug effects
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Hypothalamic Hormones / deficiency
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Hypothalamic Hormones / pharmacology*
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Immunohistochemistry / methods
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In Situ Hybridization, Fluorescence / methods
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Intracellular Signaling Peptides and Proteins / metabolism
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Melanins / deficiency
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Melanins / pharmacology*
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Mice
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Mice, Transgenic
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Neurons / metabolism
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Neuropeptides / metabolism
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Nucleus Accumbens / cytology
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Nucleus Accumbens / drug effects*
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Nucleus Accumbens / physiology
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Orexin Receptors
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Orexins
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Pituitary Hormones / deficiency
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Pituitary Hormones / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Reaction Time / drug effects
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Reaction Time / genetics
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Receptors, AMPA / metabolism
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Receptors, G-Protein-Coupled
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Receptors, Neuropeptide
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Receptors, Pituitary Hormone / antagonists & inhibitors
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Receptors, Pituitary Hormone / metabolism
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Serine / metabolism
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Swimming / physiology*
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Time Factors
Substances
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Benzazepines
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Cyclic AMP Response Element-Binding Protein
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Dopamine Agonists
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Enkephalins
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Hypothalamic Hormones
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Intracellular Signaling Peptides and Proteins
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Melanins
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Neuropeptides
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Orexin Receptors
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Orexins
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Pituitary Hormones
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Receptors, AMPA
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Receptors, G-Protein-Coupled
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Receptors, Neuropeptide
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Receptors, Pituitary Hormone
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melanin-concentrating hormone receptor
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Serine
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melanin-concentrating hormone
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SK&F 81297
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Dynorphins
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glutamate receptor ionotropic, AMPA 1