Regulation of nucleus accumbens activity by the hypothalamic neuropeptide melanin-concentrating hormone.
The lateral hypothalamus and the nucleus accumbens shell (AcbSh) are brain regions important for food intake. The AcbSh contains high levels of receptor for melanin-concentrating hormone (MCH), a lateral hypothalamic peptide critical for feeding and metabolism. MCH receptor (MCHR1) activation in the AcbSh increases food intake, while AcbSh MCHR1 blockade reduces feeding. Here biochemical and cellular mechanisms of MCH action in the rodent AcbSh are described. A reduction of phosphorylation of GluR1 at serine 845 (pSer(845)) is shown to occur after both pharmacological and genetic manipulations of MCHR1 activity. These changes depend upon signaling through G(i/o), and result in decreased surface expression of GluR1-containing AMPA receptors (AMPARs). Electrophysiological analysis of medium spiny neurons (MSNs) in the AcbSh revealed decreased amplitude of AMPAR-mediated synaptic events (mEPSCs) with MCH treatment. In addition, MCH suppressed action potential firing MSNs through K(+) channel activation. Finally, in vivo recordings confirmed that MCH reduces neuronal cell firing in the AcbSh in freely moving animals. The ability of MCH to reduce cell firing in the AcbSh is consistent with a general model from other pharmacological and electrophysiological studies whereby reduced AcbSh neuronal firing leads to food intake. The current work integrates the hypothalamus into this model, providing biochemical and cellular mechanisms whereby metabolic and limbic signals converge to regulate food intake.
Sears
Robert M
RM
Department of Psychiatry, Ribicoff Research Facilities, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Liu
Rong-Jian
RJ
Narayanan
Nandakumar S
NS
Sharf
Ruth
R
Yeckel
Mark F
MF
Laubach
Mark
M
Aghajanian
George K
GK
DiLeone
Ralph J
RJ
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D017609:Barium Compounds / Q000494:pharmacology; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D002712:Chlorides / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D007028:Hypothalamic Hormones / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008543:Melanins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000145:classification / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D010907:Pituitary Hormones / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D017609:Barium Compounds; D001710:Biotin; D002712:Chlorides; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D007028:Hypothalamic Hormones; D008543:Melanins; D010907:Pituitary Hormones; D026902:Potassium Channel Blockers; D018091:Receptors, AMPA; D012694:Serine; C070614:neurobiotin; C024986:barium chloride; C019463:melanin-concentrating hormone