Food scarcity, neuroadaptations, and the pathogenic potential of dieting in an unnatural ecology: Binge eating and drug abuse
Research highlights
► Food restriction (FR) increases behavioral responses to D-1 receptor stimulation. ► FR upregulates D-1 receptor signaling and transcription in nucleus accumbens. ► FR increases GluR1 phosphorylation in response to cocaine and sucrose. ► FR increases synaptic insertion of AMPA receptors in response to sucrose. ► FR may increase synaptic plasticity and addiction risk.
Introduction
In recent years there has been interest in the possible therapeutic use of controlled caloric restriction to induce the physiological and behavioral adaptations which accompany food scarcity in the wild. These adaptive responses are diverse and are generally aimed at conserving energy, prolonging survival, and promoting foraging and procurement of food. Consequently, caloric restriction has been reported to reduce oxidative stress, lower the risk of cardiovascular disease, increase resistance to neurotoxins, slow cognitive decline with age, and increase lifespan in many species (e.g., [1], [2], [3]). In addition, restricted feeding has been reported to exert mood-elevating and analgesic effects in humans [4], antidepressant and anxiolytic effects in animal models [5], [6], [7], [8], and increase incentive motivational responses in humans and rodents [9], [10], [11], [12], [13]. Neurophysiological correlates of the robust behavioral phenotype of the food-restricted subject were recently investigated using c-fos immunohistochemistry. Chronically food-restricted rats exposed to a nonthreatening novel environment displayed increased activation throughout a network of structures involved in antidepressant efficacy and incentive motivation, including ventral tegmental area, nucleus accumbens, and the piriform, anterior cingulate, and secondary motor cortices (Antoine, Austin, Stone and Carr, in preparation).
While controlled caloric restriction may be sustainable and beneficial when embedded within a supportive cognitive or social framework, weight-loss dieting in an ecology of abundant appetitive rewards has the potential to engender maladaptive compulsive behavior. Restrained eating often leads to loss of control, binging, and counterproductive weight gain [14], [15], [16], [17], and severe dieting is a risk factor for binge pathology [18]. Moreover, associations between food restriction, binge pathology, and substance abuse have been observed in clinical populations [19], [20], college students [21] and, most recently, high school students [22], [23]. The deliberate pairing of food restriction and drugs of abuse is not an uncommon practice, as in the use of tobacco and psychostimulants for appetite suppression [24], [25] or the increasingly popular “drunkorexia” among college-age women (i.e., fasting during the day in order to binge drink at night without weight gain) [26]. In light of the shared neural substrates of ingestive behavior and drug abuse [27], [28], [29], [30], and the neuroadaptations induced by food restriction to be described below, the neuroplastic changes which underlie drug addiction [31] may develop in response to supranormally rewarding foods, and occur more readily in response to drugs, if subjects are repeatedly exposed during food restriction.
Section snippets
Early behavioral and microdialysis studies
In the mid-1980s Bart Hoebel and colleagues developed an in vivo microdialysis system which enabled sampling of extracellular fluid in multiple small regions of rat brain [32]. Implementing this technical advance they demonstrated that systemically administered d-amphetamine increased extracellular DA concentrations [33], as did an episode of feeding in food-restricted rats, and electrical stimulation delivered via lateral hypothalamic electrodes in sites that supported feeding and
Food restriction may decrease basal dopamine activity but increases drug reward magnitude and evoked fos expression in dopamine terminal fields
To evaluate drug reward magnitude in previously drug-naïve rats, a learning-free measure was used in which subjects self-administered brief trains of reinforcing lateral hypothalamic electrical stimulation, with the available brain stimulation frequency being varied systematically over trials. In this paradigm, experimenter-administered drugs of abuse produce a leftward shift in the curve that relates rate of reinforcement to brain stimulation frequency, and the extent of this shift is taken as
Upregulated cellular responses to D-1 DA receptor stimulation: candidate mechanisms of increased drug reward sensitivity and reward-related learning
Acute challenge with the D-1 DA receptor agonist, SKF-82958, produced greater phosphorylation of ERK 1/2 MAP kinase and the downstream nuclear transcription factor CREB, and increased preprodynorphin and preprotachykinin gene expression in NAc of FR relative to AL rats [56], [57]. In addition, FR subjects displayed increased phosphorylation of the NMDA receptor NR1 subunit and CaMK II [57]. The increased activation of ERK 1/2, CaMK II and CREB were shown to be NMDA receptor-dependent in as much
Similar effects of drugs and sucrose on AMPA receptor GluR1 subunit phosphorylation
Sucrose, by way of orosensory [80], [81] and postingestive [82] signaling, leads to increased extracellular DA concentrations in NAc [83], [84]. Given the proposal that refined sugars, such as sucrose, generate a supranormal reward signal in brain (e.g., [85]), and their intermittent intake, alternated with periods of total food deprivation produces addiction-like behavior [86], we also tested whether brief intake of sucrose could increase NAc GluR1 phosphorylation in a manner similar to
DA-mediated “overlearning” in response to palatable food and drugs during food restriction?
There is evidence that mechanisms involved in synaptic plasticity that are upregulated by FR are not exclusively postsynaptic. Specifically, FR may sustain the function of NAc shell DA release as a mediator of reward-related learning. Ventral tegmental DA neuronal burst firing has been characterized as a “teaching signal” [89], and NAc convergence of DA with glutamate-coded signals arising from hippocampus, basolateral amygdala, and medial prefrontal cortex [90], [91], regulate NAc neuronal
Synaptic insertion of AMPA receptors: a new focus in the exploration of acute and enduring effects of food restriction on reward-directed behavior
It was recently observed that brief intake of sucrose by AL rats increased GluR1 abundance in the NAc postsynaptic density—a finding indicated by subcellular fractionation and Western analysis, and then confirmed by electron microscopy (Tukey, Ferreira, Antoine, Ninan, Cabeza de Vaca, Hartner, Goffer, Guarini, Marzan, Mahajan, Carr, Aoki, and Ziff, under review). In a follow-up study, we investigated whether brief intake of sucrose during FR increases trafficking of AMPA receptors to the
Concluding comment
The parallel between compulsive use of food and drugs has become a topic of interest and productive research [30], [115]. Among the risk factors that may increase vulnerability to both are food restriction and the concomitant neuroadaptations which evolved to enable survival through alternating cycles of food scarcity and abundance. Weight-loss dieting amidst an abundance of supranormally rewarding foods and cues signaling their availability is likely to be stressful and inevitably lead to
Acknowledgments
Research, by the author, reviewed in this paper was supported by DA003956 from NIDA/NIH and a NARSAD Independent Investigator Award.
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2022, Neuroscience and Biobehavioral ReviewsCitation Excerpt :In addition, knockdown of ObRb in VTA neurons of adult rats stimulates food intake, locomotor activity (Hommel et al., 2006) and food-motivated behavior (Davis et al., 2011), whereas specific knockout of ObRb in VTA DA neurons that project to the amygdala increase anxiety (Liu et al., 2011). While chronic food restriction increases burst firing of VTA DA neurons and can alter dopaminergic sensitivity to reward (Carr, 2011), leptin has consistently been shown to decrease DA neuronal activity (Domingos et al., 2011; Hommel et al., 2006; Roseberry et al., 2007; Trinko et al., 2011; van der Plasse et al., 2015). Correspondingly, increased burst firing of DA neurons is reported in mice with conditional deletion of ObRb (Liu et al., 2011).
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2019, Compulsive Eating Behavior and Food Addiction: Emerging Pathological ConstructsSynaptic changes in the hippocampus of adolescent female rodents associated with resilience to anxiety and suppression of food restriction-evoked hyperactivity in an animal model for anorexia nervosa
2017, Brain ResearchCitation Excerpt :Although the rats used in our study are not expected to carry the C-521T SNP, individual differences in the expression of dopamine receptors or of dopaminergic afferents may have enabled some to become more entrained to the feeding schedule than others. Dopaminergic modulation of the striatum has been shown to be required for entrainment of animals to a feeding schedule (Gallardo et al., 2014) and dopaminergic signaling at the cellular and behavioral levels are potentiated by FR (Carr, 2011). Since the dopaminergic potentiation of behavior includes conditioned place preference, which is a spatial cognition task requiring hippocampal connectivity to the prefrontal cortex and nucleus accumbens (Ferbinteanu and McDonald, 2001), it is possible that dopaminergic modulation of the hippocampus or of its connectivity to the prefrontal cortex contributes to better spatial cognitive performance of the FR-only and ABA rats.