title: The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance.
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.
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9070, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Georgescu
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sears
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Hommel
authors.forename: Michel
authors.initials: M
authors.lastname: Barrot
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bolaños
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: Maria A
authors.initials: MA
authors.lastname: Bednarek
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Maratos-Flier
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DiLeone
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001552:Benzazepines / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects* / Q000502:physiology; D005508:Food Deprivation / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D007028:Hypothalamic Hormones / Q000172:deficiency / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008543:Melanins / Q000172:deficiency / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D064446:Orexin Receptors; D000068797:Orexins; D010907:Pituitary Hormones / Q000172:deficiency / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D018091:Receptors, AMPA / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013550:Swimming / Q000502:physiology*; D013997:Time Factors
chemical_list: D001552:Benzazepines; D017362:Cyclic AMP Response Element-Binding Protein; D018491:Dopamine Agonists; D004399:Dynorphins; D004745:Enkephalins; D007028:Hypothalamic Hormones; D047908:Intracellular Signaling Peptides and Proteins; D008543:Melanins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D010907:Pituitary Hormones; D018091:Receptors, AMPA; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D011979:Receptors, Pituitary Hormone; D012694:Serine; C092274:melanin-concentrating hormone receptor; C019463:melanin-concentrating hormone; C067113:SK&F 81297