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 (pSer845) is shown to occur after both pharmacological and genetic manipulations of MCHR1 activity. These changes depend upon signaling through Gi/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.