Homeostatic regulation of reward via synaptic insertion of calcium-permeable AMPA receptors in nucleus accumbens

Physiol Behav. 2020 May 15:219:112850. doi: 10.1016/j.physbeh.2020.112850. Epub 2020 Feb 21.


The incentive effects of food and related cues are determined by stimulus properties and the internal state of the organism. Enhanced hedonic reactivity and incentive motivation in energy deficient subjects have been demonstrated in animal models and humans. Defining the neurobiological underpinnings of these state-based modulatory effects could illuminate fundamental mechanisms of adaptive behavior, as well as provide insight into maladaptive consequences of weight loss dieting and the relationship between disturbed eating behavior and substance abuse. This article summarizes research of our laboratory aimed at identifying neuroadaptations induced by chronic food restriction (FR) that increase the reward magnitude of drugs and associated cues. The main findings are that FR decreases basal dopamine (DA) transmission, upregulates signaling downstream of the D1 DA receptor (D1R), and triggers synaptic incorporation of calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc). Selective antagonism of CP-AMPARs decreases excitatory postsynaptic currents in NAc medium spiny neurons of FR rats and blocks the enhanced rewarding effects of d-amphetamine and a D1R, but not a D2R, agonist. These results suggest that FR drives CP-AMPARs into the synaptic membrane of D1R-expressing MSNs, possibly as a homeostatic response to reward loss. FR subjects also display diminished aversion for contexts associated with LiCl treatment and centrally infused cocaine. An encompassing, though speculative, hypothesis is that NAc synaptic incorporation of CP-AMPARs in response to food scarcity and other forms of sustained reward loss adaptively increases incentive effects of reward stimuli and, at the same time, diminishes responsiveness to aversive stimuli that have potential to interfere with goal pursuit.

Keywords: AMPA receptors; Dopamine; Food restriction; Nucleus accumbens; Reward.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism
  • Nucleus Accumbens* / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA* / metabolism
  • Receptors, Calcium-Sensing
  • Receptors, Dopamine D1 / metabolism
  • Reward
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid


  • Receptors, AMPA
  • Receptors, Calcium-Sensing
  • Receptors, Dopamine D1
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Calcium