DMV extrasynaptic NMDA receptors regulate caloric intake in rats

JCI Insight. 2021 May 10;6(9):e139785. doi: 10.1172/jci.insight.139785.


Acute high-fat diet (aHFD) exposure induces a brief period of hyperphagia before caloric balance is restored. Previous studies have demonstrated that this period of regulation is associated with activation of synaptic N-methyl-D-aspartate (NMDA) receptors on dorsal motor nucleus of the vagus (DMV) neurons, which increases vagal control of gastric functions. Our aim was to test the hypothesis that activation of DMV synaptic NMDA receptors occurs subsequent to activation of extrasynaptic NMDA receptors. Sprague-Dawley rats were fed a control or high-fat diet for 3-5 days prior to experimentation. Whole-cell patch-clamp recordings from gastric-projecting DMV neurons; in vivo recordings of gastric motility, tone, compliance, and emptying; and food intake studies were used to assess the effects of NMDA receptor antagonism on caloric regulation. After aHFD exposure, inhibition of extrasynaptic NMDA receptors prevented the synaptic NMDA receptor-mediated increase in glutamatergic transmission to DMV neurons, as well as the increase in gastric tone and motility, while chronic extrasynaptic NMDA receptor inhibition attenuated the regulation of caloric intake. After aHFD exposure, the regulation of food intake involved synaptic NMDA receptor-mediated currents, which occurred in response to extrasynaptic NMDA receptor activation. Understanding these events may provide a mechanistic basis for hyperphagia and may identify novel therapeutic targets for the treatment of obesity.

Keywords: Gastroenterology; Ion channels; Neuroscience; Obesity; Synapses.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Appetite Regulation / drug effects
  • Appetite Regulation / physiology*
  • Diet, High-Fat*
  • Eating / drug effects
  • Eating / physiology
  • Energy Intake / drug effects
  • Energy Intake / physiology*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Gastric Emptying / drug effects
  • Gastric Emptying / physiology*
  • Gastrointestinal Motility / drug effects
  • Gastrointestinal Motility / physiology
  • Medulla Oblongata / drug effects
  • Medulla Oblongata / metabolism*
  • Medulla Oblongata / physiology
  • Memantine / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Patch-Clamp Techniques
  • Piperidines / pharmacology
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Stomach
  • Vagus Nerve / drug effects
  • Vagus Nerve / metabolism*
  • Vagus Nerve / physiology


  • Excitatory Amino Acid Antagonists
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • ifenprodil
  • Memantine