Homeostatic regulation of reward via synaptic insertion of calcium-permeable AMPA receptors in nucleus accumbens
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].
References (217)
- et al.
Orexin/hypocretin system: role in food and drug overconsumption
Int. Rev. Neurobiol.
(2017) - et al.
Differential responsiveness of dopamine transmission to food-stimuli in nucleus accumbens shell/core compartments
Neuroscience
(1999) Modulation of taste affect by hunger, caloric satiety, and sensory-specific satiety in the rat
Appetite
(1991)‘Liking’ and ‘wanting’ food rewards: brain substrates and roles in eating disorders
Physiol. Behav.
(2009)- et al.
Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens
Neuron
(2012) - et al.
Inactivation of the paraventricular thalamus abolishes the expression of cocaine conditioned place preference in rats
Drug Alcohol Depend.
(2014) - et al.
Hunger-driven motivational state competition
Neuron
(2016) - et al.
The effects of prolonged caloric restriction leading to weight-loss on food hedonics and reinforcement
Physiol. Behav.
(2008) - et al.
Neural and psychological mechanisms underlying appetitive learning: links to drug addiction
Curr. Opin. Neurobiol.
(2004) - et al.
AMPA receptor subunit GluR1 downstream of d-1 dopamine receptor stimulation in nucleus accumbens shell mediates increased drug reward magnitude in food-restricted rats
Neuroscience
(2010)
Evidence of increased dopamine receptor signaling in food-restricted rats
Neuroscience
Increased drug-reinforced behavior due to food deprivation
Adv. Behav. Pharmacol.
Feeding and reward: perspectives from three rat models of binge eating
Physiol. Behav.
Dopamine in disturbances of food and drug motivated behavior: a case of homology?
Physiol. Behav.
Lateral hypothalamic neuropeptides in reward and drug addiction
Life Sci.
Diffusional trapping of GluR1 ampa receptors by input-specific synaptic activity
Neuron
Effects of deprivation on hedonics and reinforcing value of food
Physiol. Behav.
Evidence for opponent- process actions of intravenous cocaine
Pharmacol. Biochem. Behav.
Progressive ratio performance varies with body weight in rats
Behav. Process.
Individual nucleus accumbens-projection neurons receive both basolateral amygdala and ventral subicular afferents in rats
Neuroscience
Alterations in immediate-early gene proteins in the rat forebrain induced by acute morphine injection
Brain Res.
Chronic administration of morphine is associated with a decrease in surface AMPA GluR1 receptor subunit in dopamine D1 receptor expressing neurons in the shell and non-D1 receptor expressing neurons in the core of the rat nucleus accumbens
Exp. Neurol.
Examining persistence of acute environmental enrichment-induced anti-sucrose craving effects in rats
Appetite
Chronic food restriction increases d-1 dopamine receptor agonist-induced ERK1/2 MAP kinase and CREB phosphorylation in caudate-putamen and nucleus accumbens
Neuroscience
Food restriction increases NMDA receptor-mediated CaMK II and NMDA receptor/ERK 1/2-mediated CREB phosphorylation in nucleus accumbens upon d-1 dopamine receptor stimulation in rats
Neuroscience
Comparison of basal and d-1 dopamine receptor agonist- stimulated neuropeptide gene expression in caudate-putamen and nucleus accumbens of ad libitum fed and food-restricted rats
Molec. Brain Res.
The analgesia produced by food deprivation in 4-month old, 14-month old, and 24-month old rats
Life Sci.
Effects of chronic icv leptin infusion on motor-activating effects of d-amphetamine in food-restricted and ad libitum fed rats
Physiol. Behav.
Effects of central leptin infusion on the reward-potentiating effect of d-amphetamine
Brain Res.
Brain neurotransmitters in food and drug reward
Am. J. Clin. Nutr.
Reduction of anxiety after restricted feeding in the rat: implication for eating disorders
Biol. Psychiatry
Serotonin mediates cross-modal reorganization of cortical circuits
Neuron
Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning
Neurosci. Biobehav. Rev.
Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward
Physiol. Behav.
Suppressed sympathetic outflow to skeletal muscle, muscle thermogenesis, and activity energy expenditure with calorie restriction
Physiol. Rep.
Dieting and smoking initiation in early adolescent girls and boys: a prospective study
Am. J. Public Health
Rebalance of striatal NMDA/AMPA receptor ratio underlies the reduced emergence of dyskinesia during D2-like dopamine agonist treatment in experimental Parkinson's disease
J. Neurosci.
Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression
Nat. Commun.
Activation of a subpopulation of orexin/hypocretin-containing hypothalamic neurons by GABAA receptor-mediated inhibition of the nucleus accumbens shell, but not by exposure to a novel environment
Eur. J. Neurosci.
Modulation of feeding-induced activation of mesolimbic dopamine transmission by appetitive stimuli and its relation to motivational state
Eur. J. Neurosci.
Food-deprivation increases cocaine-induced conditioned place preference and locomotor activity in rats
Psychopharmacology
Topographical corticostriatal projections in the rat
J. Comp. Neurol.
Organization of the thalamostriatal projections in the rat, with special emphasis on the ventral striatum
J. Comp. Neurol.
Cellular, subcellular, and subsynaptic distribution of AMPA type glutamate receptor subunits in the neostriatum of the rat
J. Neurosci.
The debate over dopamine's role in reward: the case for incentive salience
Psychopharmacology
The interrelated mechanisms of reinforcement and motivation, and the nature of their influence on response
Diet and physical activity behaviors among Americans trying to lose weight: 2000 behavioral risk factor surveillance system
Obes. Res.
Behavioral sensitization to cocaine associated with increased AMPA receptor surface expression in the nucleus accumbens
J. Neurosci.
The patterns of afferent innervation of the core and shell in the ‘accumbens’ part of the rat ventral striatum: immunohistochemical detection of retrogradely transported fluoro-gold
J. Comp. Neurol.
Physiological role of pleasure
Science
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