The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance

J Neurosci. 2005 Mar 16;25(11):2933-40. doi: 10.1523/JNEUROSCI.1714-04.2005.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal
  • 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
  • Melanins / deficiency
  • Melanins / pharmacology*
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism
  • 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

Substances

  • Benzazepines
  • Cyclic AMP Response Element-Binding Protein
  • Dopamine Agonists
  • Enkephalins
  • Hypothalamic Hormones
  • Intracellular Signaling Peptides and Proteins
  • Melanins
  • Neuropeptides
  • Orexin Receptors
  • Orexins
  • Pituitary Hormones
  • Receptors, AMPA
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Receptors, Pituitary Hormone
  • melanin-concentrating hormone receptor
  • Serine
  • melanin-concentrating hormone
  • SK&F 81297
  • Dynorphins
  • glutamate receptor ionotropic, AMPA 1