Elsevier

Physiology & Behavior

Volume 219, 15 May 2020, 112850
Physiology & Behavior

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

https://doi.org/10.1016/j.physbeh.2020.112850Get rights and content

Highlights

  • Food restriction increases the reward magnitude of abused drugs and associated cues.

  • Behavioral effects are mediated by Ca2+-permeable AMPA receptors in n. accumbens.

  • Results may provide insight into dieting as a risk factor for binge eating and drug abuse.

Abstract

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.

Introduction

Motivational theory that preceded and influenced recent advances in behavioral neuroscience maintained that incentive properties of environmental stimuli are sufficient to drive behavior and that their potency is determined, in part, by the internal state of the organism [16]. An example of this joint regulation by internal and external factors is positive alliesthesia, in which the hedonic and incentive motivating effects of food and related cues are increased by energy deficit [23]. In animal models, sweet taste reactivity is enhanced by food deprivation [13,73], and the reinforcing potency of food measured in progressive ratio protocols of instrumental responding displays a pattern of increase that parallels body weight loss [60,88,89]. Negative energy balance therefore augments both orosensory reward and the incentive motivation that drives food seeking behavior. Both effects have been confirmed in human studies, where energy deprivation increases the “liking” [26,180,212] and “wanting” of food [54,158]. The neurocircuits that underlie hedonic reactivity and incentive motivation have been differentiated, with the former including a key opioid component, and the latter being largely dopamine mediated [36,99]. These separate but interacting [15,137,169] neurocircuits may be co-regulated when there are shifts in energy balance, though they can be differentially regulated as well, as is the case in addictive disorders where hedonic reactivity declines and incentive motivation escalates [164,165].

The discoveries of endocrine adiposity hormones and feeding-related neuropeptides with receptor populations in both the hypothalamus and mesolimbic pathway point to potential mechanistic bases for regulation of incentive motivation as a fundamental feature of homeostatic behavior [e.g., 50,93,120]. Thus, the presence of receptors for leptin, insulin, ghrelin, orexin, melanocortins, GLP-1 and other metabolic signaling peptides in the ventral tegmental area or nucleus accumbens point to multiple candidate mediators of the link between energy balance and reward. For most of these signaling molecules there is supporting, albeit incomplete and sometimes inconsistent, evidence of involvement in reward modulation [for reviews see: 6,104,120,139,156,213].

Section snippets

Probing reward modulation using drugs as proxies for food

A hypothesis that has been well supported by basic and translational studies maintains that drugs with abuse liability target a final common pathway for the positive reinforcing effects of natural rewards [90,108,209]. Much of the supporting research has focused on the relationship between mechanisms regulating ingestive behavior and drug abuse [28,49,101,204], with the most studied link between the two being the mesoaccumbens dopamine (DA) pathway [7,8,14,59,80,102,141,146,153,157,178,187, 210

Dopamine-related changes induced by food restriction

The food restriction protocol used in our behavioral studies (i.e., maintenance at 80% of pre-restriction body weight for a minimum of 3–4 weeks), or one very similar to it [154,155], induces a number of changes in the mesoaccumbens DA pathway. Glutamate currents in putative ventral tegmental DA neurons [147], basal DA synthetic activity in NAc, [148], and evoked DA release in NAc slices are all decreased [182]. Basal extracellular NAc DA concentrations in vivo are also decreased [154,155], as

AMPA receptor-related changes induced by food restriction

The DA innervation of NAc is convergent with several forebrain glutamate inputs [75] and AMPARs are co-expressed with DA receptors in NAc neurons [12,68]. Most are either GluA1/GluA2 or GluA2/GluA3 heteromers [159]. Changes in AMPA receptor abundance in the synaptic membrane mediate dynamic tuning of synaptic transmission as well as plasticity [40,103]. In cultured MSNs, D1R activation rapidly increases GluA1 surface expression in a PKA-dependent manner [37,126]. It is therefore noteworthy that

Glutamate inputs to nucleus accumbens

Many distinct components of reward-related behavior are encoded by NAc neurons [170], and strong evidence indicates that orosensory reward and consummatory behavior are initiated and sustained by neuronal inhibition [5,57,100,110,124,160,167,168,183,191,206]. Recently, O'Connor and coworkers identified D1R-expressing MSNs in NAc medial shell that project to lateral hypothalamus as the specific sub-population whose inhibition drives consummatory behavior [142]. In contrast, incentive motivation,

Synaptic insertion of CP-AMPARs and motivational valence

In addition to increasing the unconditioned rewarding effects of abused drugs, FR increases the magnitude and persistence of a cocaine conditioned place preference (CPP) acquired during a prior ad libitum (AL) fed state [215], [216], [217]. The same effect is seen in morphine CPP [98]. Further, in both cases, CPP expression was associated with increased NAc pSer845-GluA1, which correlated with magnitude of CPP. However, when a LiCl place aversion was conditioned, and subjects were switched to

The triggering condition for NAc neuroadaptations

The triggering condition for NAc synaptic incorporation of CP-AMPARs during FR has not been identified, though reward deficiency and the neurochemical concomitant of decreased DA transmission merit investigation. There are several other conditions in which loss of reward is followed by synaptic incorporation of CP-AMPARs in NAc. These include withdrawal from chronic cocaine [41], amphetamine [96], morphine [87], ‘junk food’ [143], and ventral tegmental DA neuronal stimulation [149]. Moreover,

Translation and caveats

The basic science findings relating to food restriction, dopamine, AMPA receptors, and drugs of abuse were obtained in male rats. This points to a serious gap in the literature. National surveys in the US indicate that at any given time twice as many women as men are dieting to lose weight [17,162,174,207], and women consistently seek to lose a greater percentage of body weight than men [17,58,112]. Moreover, transition from dieting to an eating disorder occurs predominantly in girls and women

Acknowledgement

This work was supported by the National Institutes of Health [DA-003956].

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