The Dark Side of Food Addiction
Abstract
In drug addiction, the transition from casual drug use to dependence has been linked to a shift away from positive reinforcement and towards negative reinforcement. That is, drugs ultimately are relied on to prevent or relieve negative states that otherwise result from abstinence (e.g., withdrawal) or from adverse environmental circumstances (e.g., stress). Recent work has suggested that this “dark side” shift also is key in the development of food addiction. Initially, palatable food consumption has both positive reinforcing, pleasurable effects and negative reinforcing, “comforting” effects that can acutely normalize organism responses to stress. Repeated, intermittent intake of palatable food may instead amplify brain stress circuitry and downregulate brain reward pathways such that continued intake becomes obligatory to prevent negative emotional states via negative reinforcement.
Stress, anxiety and depressed mood have shown high comorbidity with and the potential to trigger bouts of addiction-like eating behavior in humans.
Animal models indicate that repeated, intermittent access to palatable foods can lead to emotional and somatic signs of withdrawal when the food is no longer available, tolerance and dampening of brain reward circuitry, compulsive seeking of palatable food despite potentially aversive consequences, and relapse to palatable food-seeking in response to anxiogenic-like stimuli.
The neurocircuitry identified to date in the “dark” side of food addiction qualitatively resembles that associated with drug and alcohol dependence.
The present review summarizes Bart Hoebel’s groundbreaking conceptual and empirical contributions to understanding the role of the “dark side” in food addiction along with related work of those that have followed him.
1. Introduction
Drug addiction is a chronic, relapsing disorder with three distinct phases:
a binge intoxication phase driven and characterized by the rewarding properties of the drug
a withdrawal phase accompanied by a negative emotional state as the acute rewarding drug properties wear off
a preoccupation and anticipation phase that precedes renewed drug intake
Dr. Bartley Hoebel is among the very earliest pioneers who hypothesized that intake of sugar, and perhaps of other palatable foods, also could become governed by these three phases of addiction. His leadership has been instrumental not only in bridging the fields of addiction and feeding behavior through his experimental work, but also in his efforts to increase awareness of and legitimize what once was an unpopular and even controversial hypothesis within the scientific community – that one could become “food addicted.” Now, food addiction symposiums, such as the Food & Addiction Conference on Eating and Dependence hosted by the Rudd Center for Food Policy and Obesity at Yale, the “Food Addiction: Fact or Fiction” session at the 2008 Experimental Biology meeting in San Diego, and the Obesity and Food Addiction Summit of 2009, regularly bring together scientists, physicians, public policy makers, and health advocates from diverse backgrounds. Further, Dr. Hoebel’s groundbreaking work has helped spur the creation of institutes devoted specifically to advancing food addiction research, including the Food Addiction Institute and the Refined Food Addiction Research Foundation.
As drug users progress from casual use to addiction, the factors motivating drug use are hypothesized to shift in importance. While initial use is motivated by the hedonically rewarding properties of the drug, use in addicts is hypothesized to become motivated less by positive reinforcement (e.g., a euphoric high), but rather by negative reinforcement: to prevent or relieve a negative emotional state that arises from abstinence (e.g., drug withdrawal) or from adverse experience of the environment (e.g., stress) [1]. At the neurobiological level, this shift corresponds to a downregulation of brain reward systems that subserve appetitive responses to the drug and a concurrent amplification of brain stress or “antireward” systems. In this framework, the shift to the “dark side” of food addiction may similarly be conceptualized as a key transition in the addiction process. As individuals progress towards compulsive intake of palatable foods, the acute rewarding value of food items may hold less importance for motivating additional intake than does preventing or ameliorating negative states (e.g., anxiety, depression, irritability, and possibly even somatic withdrawal symptoms) that are experienced when such preferred foods are not available or when environments are adverse.
2. Evidence for the “dark side” from human studies
To determine whether an addiction-like “dark side” motivates intake of palatable food, a useful starting point is to identify the human population(s) whose eating habits most closely resemble addictive behaviors. Although obesity and addiction-like eating behaviors likely overlap, “food addiction” is unlikely to explain all cases of human obesity, and some normal weight individuals likely engage in addiction-like eating patterns. No consensus diagnostic criteria for “food addiction” currently exist [2, 3]. Recently, however, the Yale Food Addiction Scale (YFAS) has been introduced as an index of addictive-like eating behaviors that mimic the diagnostic criteria for substance dependence in the DSM-IV-TR [4]. The YFAS measures the extent to which (a) individuals overeat specific foods despite repeated attempts to limit their consumption, (b) their eating behaviors interfere with social and professional activities, and (c) withdrawal symptoms emerge when abstaining from specific foods. Preliminary application of these criteria suggest that the compulsive, uncontrollable intake of greater-than-expected amounts of food seen in binge eating disorder maps most neatly onto the current diagnostic criteria for substance dependence. Accordingly, scores on the YFAS predicted binge eating behavior and emotional eating [4] but did not correlate with body mass index (BMI) in women participating in a weight maintenance trial who reported no eating disorder [5]. These results suggest that the “dark side” of food addiction, as operationalized by the YFAS, might be more fruitfully studied in individuals with binge eating than in randomly selected obese individuals.
2.1 Psychiatric comorbidity in binge eating
Consistent with a possible role for a “dark side” in food addiction, binge eaters have greater rates of psychiatric diagnoses involving negative emotional states compared to the general population. For example, adults and adolescents with bulimia nervosa or binge eating disorder show increased prevalence of major depression, bipolar disorder, anxiety disorders, and alcohol or drug abuse than do individuals without an eating disorder [6-8]. Rates of major depression are also elevated in the obese, but the association of binge eating with increased depression scores remains even in weight-matched comparisons of overweight and obese individuals [9]. Extremely high rates of suicidal ideation in binge eaters attest to the severity of mood disturbance in this population. Over half of teenage bulimics and one-third of those with binge eating disorder report suicidal ideation, and a third of teenage bulimics report attempting suicide [6]. The direction of causality between binge eating and major depression is not firmly established and may be reciprocal [10-12]. Such psychiatric comorbidity is associated with poor long-term treatment outcome [13] and a greater frequency of binge eating [14]. Conversely, many antidepressants, such as SSRIs or tricyclics, can reduce the frequency and severity of binge eating symptoms [15].
2.2 Negative emotional states increase palatable food intake in vulnerable populations
The prevalence and severity of depression and anxiety in binge eaters suggests the hypothesis that negative emotional states can trigger relapse to bingeing behavior. Indeed, self-reported negative emotional traits of depression, low self-esteem, and neuroticism are associated with binge eating in both men and women [16]. During negative emotional states and situations, normal and underweight individuals report consuming less food than during positive emotional states and situations. In contrast, this undereating in response to negative states is not observed in overweight individuals, who report eating significantly more during negative states than do other groups [17]. Consistent with a role for negative emotional states in driving binge behavior, mood scores in bulimics are lower immediately prior to a binge than on days when no binges occur [18].
Another construct that implicates stress and negative emotions as triggers of overeating is dietary restraint. Attempts to control body weight (e.g. via dieting, exercise, appetite suppressants, or laxatives) are paradoxically associated with increased weight gain in female adolescents [19]; dietary restriction similarly is associated with long term weight gain in female adults [20]. A possible explanation for these apparent contradictions is the consistent finding that restrained eaters overeat in response to a variety of stressful situations [21]. For example, anticipation of a social stressor (a public speaking task) increased food intake in restrained eaters while not altering that of unrestrained eaters [22]. Similarly, restrained eaters who reported high subjective stress and negative affect following a series of cognitive tasks showed greater intake after the stressor than did those reporting low levels of subjective stress [23]. Dietary restraint also may have temporarily restricted importance in binge eaters because the intent to restrict intake is greater prior to a binge as compared to days on which no binges occur [18].
Though laboratory mood induction studies may be criticized as not modeling real world eating practices under natural mood conditions [24], they also broadly support the “dark side” hypothesis that overeating can be triggered by stressful or negative emotional responses in subsets of individuals. For example, obese binge eaters consumed significantly more chocolate after viewing a sad film in a laboratory setting than following a neutral film [24]. All participants in this study reported mood as one of their triggers to binge eat, with “depression” or “sadness” most often implicated. In non-obese females, those with greater salivary cortisol responses to a battery of social stressors ate more after the stressful experience than did those with lower cortisol responses [25]. Induction of a negative emotional state via autobiographical recall of a sad memory also increased the amount of snack food consumed in a study of non-dieters, and the effect was particularly pronounced in participants who reported greater “emotional eating” [26]. Unlike the reviewed findings and what occurred in restrained eaters, unrestrained eaters reduced their snack food intake after viewing a sad film [27, 28].
Such negative affect-driven food intake can disrupt body weight maintenance. Weight regain in the 6 months following successful weight loss is associated with eating in response to stressful life events, eating in response to negative mood, and the use of food to regulate mood [29]. Perhaps accordingly, adding cognitive therapy to help manage general mood and coping, and not only eating behavior and diet, can reduce relapse to obesity [30]
2.3 Influence of palatable food intake on mood and reward function
Eating in response to emotionally negative situations suggests that overeating may be an attempt to self-medicate with “comfort food.” The typical foods consumed during a binge tend to be palatable and energy dense; further, they often are carbohydrate-laden items such as breads, pastas, and sweets [31]. Initially, such carbohydrate-rich foods may have the intended negative reinforcement effect, because they reduce subjective reports of anger [32] and tension [33] and increase calmness within 1-2 hr of consumption. Repeated overconsumption of such palatable foods, however, may produce long term neuroadaptations in brain reward and stress pathways that ultimately promote depressive or anxious responses when those foods are no longer available or consumed. Consistent with this “dark side” hypothesis, after eating a high fat diet (41%) for one month, men and women who were switched to a lower-fat (25%), high-carbohydrate diet reported increased anger and hostility during the subsequent month than did subjects who continued eating the high fat diet [34]. Increased anger may have resulted either from the reduction in dietary fat (or perceived palatability) or from neuroadaptations to increased dietary carbohydrates.
Repeated overconsumption of highly palatable foods may downregulate dopaminergic reward circuitry via mechanisms that mirror those commonly observed in drug addiction: reduced striatal dopamine D2 receptor availability and blunted dopamine release [35, 36]. Indeed, obese individuals show lower striatal availability of the dopamine D2 receptor than do non-obese controls, and this reduction in striatal D2 is correlated directly with BMI [37, 38]. Caudate activation in response to a chocolate milkshake is also reduced in obese relative to lean individuals [39]. This blunted activity level is especially pronounced in individuals with the TaqIA A1 polymorphism of the D2 receptor, which is associated with reduced D2 receptor expression [39]. Another polymorphism linked to reduced dopamine function, the 7R allele of the dopamine D4 receptor, has been associated with higher lifetime maximum BMI in bulimics [40] as well as with binge eating behavior in women with seasonal depression [41]. The collective genetic data suggest a predisposition towards weight gain in individuals with low striatal dopaminergic signaling, and it has been hypothesized that such individuals overeat in an attempt to compensate for a perceived reward deficit. Recent data suggest, however, that weight gain (or a correlate of weight gain, perhaps overeating palatable food) downregulates striatal dopamine activity. Women whose BMI increased during a 6 month period showed reduced caudate activation to consumption of a chocolate milkshake than did women whose BMI remained stable, and the reduction in caudate activation was associated with greater BMI increases [42]. Conversely, gastric bypass increased striatal D2 receptor availability within 6 weeks of bariatric surgery in a small study of severely obese women [43].
Striatal D2 receptor availability in obese subjects also correlates directly with glucose metabolism in frontal cortical regions that subserve inhibitory control, including dorsolateral prefrontal, orbitofrontal, and anterior cingulate cortices [38]. This relationship suggests the hypothesis that reduced dopaminergic modulation from the striatum may lead to impaired inhibitory control over food intake and thereby increase risk of overeating. Perhaps analogously, a direct correlation between striatal D2 availability and glucose metabolism in dorsolateral and anterior cingulate cortices also has been observed in alcoholics, but not in non-alcoholics or non-obese controls [38, 44].
Consistent with reviewed behavioral differences in the ingestive response to stress, eating style also differentiates subpopulations with distinct mesolimbic dopamine system profiles. Non-obese individuals who reported greater “emotional eating” showed reduced baseline D2 receptor availability in the dorsal striatum as compared to non-emotional eaters; those high in dietary restraint had increased D2 binding in the dorsal striatum in response to food stimulation as compared to those low in dietary restraint [45]. Finally, obese binge eaters showed increased D2 receptor binding in the caudate in response to a combination of food stimulation and methylphenidate challenge as compared to obese non-binge eaters [44, 46].
3. Evidence for the “dark side” from animal models of food addiction
The development of animal models was key for validating the concept of food addiction and beginning to characterize its “dark side.” Bart Hoebel’s group has led the way in modeling aspects of food addiction in rodents [47]. While animal models cannot encompass all of the complex social factors that influence eating behavior in humans, they have the advantage of more easily distinguishing between antecedents and consequences of addictive-like eating behavior, establishing tighter dietary control, and allowing for a more detailed examination of the associated molecular mechanisms.
3.1 Induction of withdrawal-like states after cessation of palatable food access
Consistent with the “food addiction” hypothesis pioneered by Hoebel and colleagues, numerous studies in animal models have now observed behavioral and somatic profiles that resemble withdrawal-like states in animals withdrawn from intermittent access to palatable food. For example, Hoebel and colleagues provided evidence that daily bingeing on high sugar solutions (e.g., 25% glucose or 10% sucrose) may lead to endogenous opioid dependence. Rats provided with daily 12-hr access to glucose and chow alternated with 12-hr food deprivation displayed somatic signs associated with opiate withdrawal, including teeth chattering, forepaw tremors, and head shakes, when challenged with the opioid antagonist naloxone [48]. Precipitated withdrawal via naloxone pretreatment also increased anxiety-like behavior in 12-hr daily glucose-cycled animals, as shown by reduced open arm time on the elevated plus-maze, but not in animals receiving ad lib access to chow or glucose [48]. In the absence of naloxone pretreatment, somatic signs of withdrawal also occurred “spontaneously” 24-36 hr after the last glucose access session. In the absence of naloxone challenge, increased anxiety-like behavior on the plus-maze also was seen in sucrose-cycled animals after a 36-hr fast, as compared to ad lib chow fed controls, providing evidence for a heightened anxiety-like state in cycled animals withdrawn from intermittent access to a sugar solution [49].
Hoebel and colleagues have hypothesized that reduced reward function and increased anxiety-like behavior during withdrawal may originate in part from alterations in the balance of dopaminergic and acetylcholinergic (ACh) signaling within the striatum. They found that naloxone challenge stimulated significantly greater ACh release in the nucleus accumbens (NAc) of rats with a cyclic history of daily 12-hr glucose and chow access followed by a 12 hr food deprivation than in animals maintained on ad lib chow [48]. This amplification of the ACh response is accompanied by a reduction in extracellular accumbens dopamine following naloxone challenge, similar to what occurs during morphine withdrawal [50, 51]. After a 36-hr fast, glucose/chow-cycled animals have lower dopamine and higher ACh levels extracellularly in the NAc even in the absence of naloxone, again resembling a spontaneous opiate withdrawal-like state during abstinence from the glucose diet [49]. Hoebel and colleagues propose that this shift towards enhanced ACh release concurrent with diminished dopamine release may reflect a broader behavioral shift away from dopamine-mediated approach behaviors and towards harm avoidance [52].
Using a sugar-rich solid diet, rather than a liquid diet, Cottone et al. similarly found spontaneously increased anxiety-like behavior in rats withdrawn from intermittent access to a high-sucrose, chocolate-flavored diet. Rats provided with alternating 5-day/2-day access to standard laboratory chow and the palatable diet spent less time on the open arms of the elevated plus-maze and more time within the withdrawal chamber in a defensive withdrawal task when tested during the chow phase of their diet cycle [53, 54]. The increase in anxiety-like behavior was accompanied by increased expression of the stress-related neuropeptide corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA), a system that also is activated during withdrawal from alcohol [55-59], opiates [60-63], cocaine [64], cannabinoids [65],and nicotine [66, 67]. Pretreatment with the selective CRF1antagonist R121919 blocked the food withdrawal-associated anxiety at doses that did not alter behavior of chow-fed controls [68-70]. Analogously, CRF1 antagonists ameliorated aversive- or anxiety-like states during withdrawal from alcohol [59, 71, 72], opiates [73, 74], benzodiazepines [75], cocaine [76, 77], and nicotine [66]. CRF1antagonist pretreatment also blunted the degree to which diet-cycled animals overate the sucrose-rich diet upon renewed access at doses that did not alter intake of chow-fed controls or of animals fed the sucrose-rich diet, but without a history of diet cycling. Analogously, CRF1 antagonists reduce excessive intake of alcohol [57, 78-82], cocaine [83], opiates [84], and nicotine [66] in models of addiction, while having lesser effects on drug and alcohol self-administration of non-dependent animals.
When diet-cycled animals were studied while receiving access to the preferred, sucrose-rich diet, both plus-maze behavior and CeA CRF levels normalized, supporting the hypothesis that increased activation of the amygdala CRF system and anxiety-like behavior reflected an acute withdrawal state [53, 54]. Finally, diet-cycled rats also showed increased sensitivity of CeA GABAergic neurons to modulation by CRF1 antagonism. R121919 reduced evoked inhibitory postsynaptic potentials in the CeA to a greater degree in diet-cycled rats than in chow-fed controls, mirroring the enhanced modulatory influence of CRF1 antagonists on CeA GABAergic synaptic transmission that is seen during withdrawal from alcohol [58]. Thus, the pattern of palatable food withdrawal-associated increases in CeA CRF expression and anxiety-like behavior, escalation of intake upon renewed access, and reversal of behavior via CRF1 antagonist pretreatment resembles findings in both drug and alcohol addiction [68-70].
In a separate study, Cottone et al. also found that female rats with a history of receiving highly limited (10 min/day) access to the same chocolate-flavored, sucrose-rich diet exhibited not only dramatic escalation of their intake of the palatable diet (consuming over 40% of their daily intake within 10 min), but also an anxiogenic-like reduction in plus-maze open arm time when studied 24 hr after their last access session [85]. Diet-cycled rats that spent the least time on the open arms were also those that binged the most on the palatable diet, a correlation not evident in chow-fed controls. These results support the Hoebel hypothesis that intermittent access to a palatable sucrose-rich diet leads not only to binge-like intake of the diet, but also to a withdrawal-like state of increased anxiety in direct relation to the binge-like eating.
3.2 Sugar vs. fat addiction: Is there a difference?
Hoebel and colleagues also have recently proposed that there may be something different about the ability of simple sugars (vs. fats) to promote “food addiction” [86]. Whereas somatic and anxiety-like signs of withdrawal have been observed following cessation of intermittent access to sugar solutions or solid diets, the case for withdrawal signs following diets consisting predominantly of fat or sweet-fat mixtures is less clear. As with sugar diets, rats develop binge-like eating patterns when receiving intermittent access to pure fats such as vegetable shortening [87] and sweet-fat chow mixtures [88]. Unlike the robust findings of opiate-like withdrawal in glucose-cycled rats, however, naloxone challenge and fasting have failed to produce opiate-like somatic withdrawal signs in rats with intermittent access to vegetable fat or sweet-fat chow [86].
Still, a lack of somatic opiate withdrawal-like signs does not preclude the possible development of a negative emotional state in animals withdrawn from high-fat food (i.e. “affective withdrawal”). Indeed, some have observed altered behavioral responses to mild stressors after removal of a preferred high fat diet. Mice maintained continuously on a high-fat diet showed increased activity in the open field test 24 hr after being switched to standard chow, an effect not seen in rats withdrawn from a high-sucrose diet [89]. Moreover, 24-hr withdrawal from high fat diet also resulted in increased CRF mRNA levels in the CeA [89], similar to the findings of Cottone et al. with a sucrose-rich diet [53]. On the other hand, group differences were not observed in other indices of anxiety-like behavior, including marble burying or elevated plus-maze behavior. Additional considerations for interpreting results from this experiment vis-à-vis previously reviewed studies of sugar “withdrawal” include that the palatable diets were provided continuously rather than intermittently; that the high-fat diet here was more preferred than the high-sucrose diet; and that the high-sucrose diet was an admixture of macronutrients, rather than a predominantly or pure sugar diet.
Withdrawal-like signs of anxiety upon removal of a palatable diet also may be moderated by genetic factors. Cottone et al. observed stable individual differences in the degree to which rats binged on a high-sucrose diet that correlated with their degree of anxiety-like behavior 24-hr post-access [85]. Pickering et al. found that obesity-prone, but not obesity-resistant, rats showed reduced activity in the center of an open field 2 weeks after being switched to a standard chow diet subsequent to 7 weeks of access to a palatable high-fat, high-sugar diet [90]. The obesity-prone animals continued to undereat the chow relative to both chow-only controls and obesity-resistant animals across three weeks of withdrawal.
Rodents withdrawn from preferred diets will also endure negative consequences to obtain renewed access [89, 91]. For example, mice withdrawn from a high-fat diet spent more time in a brightly-lit aversive environment where they can eat a high-fat pellet than did mice not withdrawn from the high fat diet or chow-fed controls [89]. Rats with a history of extended access to a palatable cafeteria diet also did not reduce responding for the palatable diet despite the presence of a footshock-conditioned cue [91]. The latter behavior resembles the persistence of cocaine-seeking behavior in rodents despite the presence of a cue that predicts footshock. The results suggest the development of compulsive eating patterns, perhaps analogous to compulsive drug intake, that are resistant to potentially aversive outcomes [92].
3.3 Stress-induced food-seeking and intake
Because palatable food can have negative reinforcing, or “comforting,” effects, heightened anxiety and stress are not merely consequences of being withdrawn from a palatable diet, but also motivating factors that promote relapse to increased intake after a period of abstinence. By extension, increases in the motivation to obtain, consume and select palatable “comfort” foods under environmental stress can be hypothesized to reflect negative reinforcement processes analogous to those operating during withdrawal from palatable food [49, 54, 93, 94]. The well-established ability of consumption of palatable foods under certain conditions to attenuate exogenous activation of stress systems, as evidenced in behavioral, autonomic, neuroendocrine, and neurochemical measures [94-111], strongly supports this hypothesis.
Perhaps accordingly, the alpha-2 adrenergic antagonist yohimbine, a pharmacological stressor that produces high anxiety states in humans and rodents, and that triggers reinstatement of cocaine-, alcohol-, and methamphetamine-seeking behavior in rats [112-114], also triggers reinstatement of responding for palatable food pellets and sucrose solutions [115-117]. Yohimbine induces reinstatement of seeking for a variety of energy-containing food pellets, including non-sucrose carbohydrate, sucrose and high-fat pellets, but not of energy-devoid and, perhaps also less palatable, cellulose fiber pellets [118]. Multiple neurotransmitter systems have been implicated as downstream modulators of this effect, including the CRF, orexin, and dopaminergic systems. Systemic pretreatment with the CRF1 receptor antagonist antalarmin strongly attenuates yohimbine-induced reinstatement of palatable food seeking [115], as does pretreatment with the orexin-1 antagonist SB334867[117]. The site(s) of action for these compounds in blocking yohimbine-induced reinstatement remains unknown. Based on the neuroanatomy of stress- or yohimbine-induced reinstatement of drug seeking [119], however, regions involved in the extended amygdala or in inhibitory control are plausible candidates. Indeed, microinjection of CRF into the nucleus accumbens can potentiate cue-induced responding for sucrose [120] and administration of the dopamine D1 antagonist SCH23390into the dorsomedial prefrontal cortex can attenuate yohimbine-induced reinstatement of food seeking [121].
Stressful environmental conditions also can promote ongoing intake of palatable foods by rodents. Under chronic variable stress, mice select more of their daily caloric intake from a high fat diet than from high protein or high carbohydrate diet options [111]. CRF2 deficient mice, which show an exaggerated HPA-axis response to stress, increase their intake of high fat diet following chronic variable stress to a greater degree than do wild type controls, if the high fat diet is provided for 1hr daily rather than ad libitum. These mice also show a reduction in CORT release to restraint stress after 2-3 weeks of concurrent exposure to high fat, carbohydrate, and protein diets during chronic variable stress [111].
Boggiano and colleagues have identified a synergistic relationship between food restriction and stress in promoting binge-like food intake in rats that may model the previously reviewed interaction of dietary restraint and stress in triggering binge eating in humans. In the model, neither a history of caloric restriction nor footshock stress alone are sufficient to promote binge-like eating relative to unstressed+unrestricted chow-fed rats. Rather, the combination of repeated cycles of dietary restriction+footshock leads to increased intake of palatable food (cookies) following the stressor [122, 123]. The increased intake is not driven by current metabolic need because the diet schedule allows restricted groups to re-feed on chow to normal body weight prior to the footshock challenge [124]. If only standard chow is available, no binge-like behavior occurs, but if a small sample of palatable food is provided alongside the standard chow diet, then the rats proceed to binge on chow. These data echo findings from human bulimics, who are much more likely to initiate a binge (on any food) if they first consume a craved food [125]. Other groups have observed similar binge-like behavior following a history of cyclic food restriction if the footshock stressor is replaced with a 15-min period of visual and olfactory exposure to palatable food, during which consumption is not permitted [126]. Although the precise neurobiological changes induced by repeated cycles of restriction, stress, and refeeding remain to be elucidated, endogenous opioids may contribute to the stress-triggered binge-like behavior. Naloxone challenge decreases and the mu/kappa agonist butorphanol increases palatable food intake in the restricted+stressed group specifically [127],
3.4 Loss of hedonic value of previously rewarding stimuli
One of the hallmarks of the “dark side” of drug addiction is the development of tolerance, in which larger and larger quantities of drug are required to produce the same hedonic effect. Lesser quantities are no longer perceived as rewarding. A similar loss of hedonic response to food rewards may occur in animals with a history of palatable food access. Indeed, Hoebel and colleagues observed dramatic increases in glucose intake over successive days of 12-hr limited access and increasingly rapid glucose consumption during the first hour of access, consistent with the development of tolerance and a shift towards binge-like eating [128] Enhanced motivation to obtain the glucose diet was also observed following a two week period of abstinence [47]. Other investigators have since replicated such binge-like escalation that may indicate tolerance using a variety of diets and degrees of limited access [85, 87, 129, 130].
Also potentially resembling tolerance, other previously acceptable rewards become less effective at supporting operant responding and engaging mesolimbic reward circuitry. Rats receiving intermittent access to a chocolate-flavored, sucrose-rich diet develop progressively lower break points when asked to respond for a less preferred, but otherwise palatable, corn-syrup sweetened chow on a progressive ratio schedule [53]. Motivational deficits to obtain the less preferred food are reversed by pretreatment with a CRF1 antagonist, perhaps analogous to the ability of a CRF1 antagonist to reverse blunted reward function during nicotine withdrawal [131].
Other evidence of reduced responses to less palatable, alternative rewards comes from microdialysis experiments in which extracellular dopamine levels were measured in rats with a history of cafeteria diet access. Cafeteria-diet feeding results in lower basal levels of dopamine in the nucleus accumbens after 14 weeks of access, and lower stimulation-evoked dopamine release in both the accumbens and dorsal striatum [132]. In chow-fed rats, increases in dopamine efflux were observed in response to a meal of standard laboratory chow, whereas this increase was no longer observed in the cafeteria-diet fed rats. Dopamine efflux in response to an alternative rewarding stimulus, amphetamine, was also markedly diminished in the cafeteria-diet fed rats. The cafeteria diet, however, continued to stimulate dopamine efflux in the accumbens, suggesting that continued consumption of the cafeteria diet is required for these animals to avoid a chronic dopamine release deficit [132]. Intermittency of access to a palatable diet may also impact its ability to sustain striatal dopamine release. In rats with 12-hr intermittent access to sucrose, sucrose continues to stimulate dopamine efflux in the accumbens after three weeks, but this effect is lost in animals with ad libitum sucrose access [133].
Intracranial lateral hypothalamic self-stimulation thresholds also increase in rats provided with extended, but not limited, access to a palatable cafeteria diet. [91]. Elevated self-stimulation thresholds, an index of impaired brain reward function, arise concurrently with the development of diet-induced obesity and persist even after forced abstinence from the cafeteria diet for a period of two weeks. Analogous to previously reviewed findings in humans, striatal dopamine D2 receptor levels are also markedly reduced after extended access to the cafeteria diet; lentivirus-mediated knockdown of D2 receptor expression accelerated the increase in reward thresholds, implicating a causal role for this diet-induced neuroadaptation in subsequent brain reward system dysfunction [91]. Reductions in striatal D2 binding [134] and D2 receptor mRNA [135] have also been observed in response to daily, binge-like limited access to sucrose, while D3 receptor mRNA and dopamine transporter expression are increased [136]. Dampened mesolimbic dopaminergic transmission may have functional implications for risk of weight gain, because obesity-prone rats have lower basal extracellular dopamine levels in the accumbens than do obesity-resistant rats even prior to weight divergence, and injection of a lipid emulsion fails to increase accumbens dopamine levels in the obesity-prone group [137]. In contrast, food restriction is associated with increases in D2 levels in obese Zucker rats [138]. As a whole, the results suggest that palatable food consumption can lead to lasting impairments in brain reward systems.
4. Conclusions
Just as the transition from drug use to dependence is accompanied by a downregulation of brain reward circuitry and a concurrent enhancement of “anti-reward” circuitry, so does the transition to food addiction appear to involve a “dark side.” Studies of human binge eaters, whose behavior most closely aligns with the current conception of food addiction, have implicated stress and anxious and depressive mood states in the development and maintenance of this transition to consuming palatable food for its negative reinforcing effects.
Animal studies, initiated in large part by Bart Hoebel’s group and now gaining in momentum, have begun to clarify the specific roles of diet schedule, composition, and palatability in altering behavioral, neural, and endocrine stress systems as well as in dampening hedonic responses to food and alternative rewards. However, significant challenges remain. Further work is needed to reach consensus on diagnostic criteria for food addiction in humans. Refinement of such criteria will further the development of suitable animal models to better study the most critical aspects of this disorder.
References
1. Koob GF, Le Moal M. Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction. Nat Neurosci. 2005;8:1442–4. [PubMed] [Google Scholar]
2. Ifland JR, Preuss HG, Marcus MT, Rourke KM, Taylor WC, Burau K, et al. Refined food addiction: a classic substance use disorder. Med Hypotheses. 2009;72:518–26. [PubMed] [Google Scholar]
3. Moreno C, Tandon R. Should Overeating and Obesity be classified as an Addictive Disorder in DSM-5? Curr Pharm Des. 2011 [PubMed] [Google Scholar]
4. Gearhardt AN, Corbin WR, Brownell KD. Preliminary validation of the Yale Food Addiction Scale. Appetite. 2009;52:430–6. [PubMed] [Google Scholar]
5. Gearhardt AN, Yokum S, Orr PT, Stice E, Corbin WR, Brownell KD. Neural Correlates of Food Addiction. Arch Gen Psychiatry. 2011 [PMC free article] [PubMed] [Google Scholar]
6. Swanson SA, Crow SJ, Le Grange D, Swendsen J, Merikangas KR. Prevalence and Correlates of Eating Disorders in Adolescents: Results From the National Comorbidity Survey Replication Adolescent Supplement. Arch Gen Psychiatry. 2011 [PMC free article] [PubMed] [Google Scholar]
7. Mitchell JE, Mussell MP. Comorbidity and binge eating disorder. Addict Behav. 1995;20:725–32. [PubMed] [Google Scholar]
8. Hudson JI, Hiripi E, Pope HG, Jr, Kessler RC. The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry. 2007;61:348–58. [PMC free article] [PubMed] [Google Scholar]
9. Galanti K, Gluck ME, Geliebter A. Test meal intake in obese binge eaters in relation to impulsivity and compulsivity. Int J Eat Disord. 2007;40:727–32. [PubMed] [Google Scholar]
10. Stice E, Hayward C, Cameron RP, Killen JD, Taylor CB. Body-image and eating disturbances predict onset of depression among female adolescents: a longitudinal study. J Abnorm Psychol. 2000;109:438–44. [PubMed] [Google Scholar]
11. Stice E, Killen JD, Hayward C, Taylor CB. Age of onset for binge eating and purging during late adolescence: a 4-year survival analysis. J Abnorm Psychol. 1998;107:671–5. [PubMed] [Google Scholar]
12. Spoor ST, Stice E, Bekker MH, Van Strien T, Croon MA, Van Heck GL. Relations between dietary restraint, depressive symptoms, and binge eating: A longitudinal study. Int J Eat Disord. 2006;39:700–7. [PubMed] [Google Scholar]
13. Fichter MM, Quadflieg N, Hedlund S. Long-term course of binge eating disorder and bulimia nervosa: relevance for nosology and diagnostic criteria. Int J Eat Disord. 2008;41:577–86. [PubMed] [Google Scholar]
14. Peterson CB, Miller KB, Crow SJ, Thuras P, Mitchell JE. Subtypes of binge eating disorder based on psychiatric history. Int J Eat Disord. 2005;38:273–6. [PubMed] [Google Scholar]
15. Brownley KA, Berkman ND, Sedway JA, Lohr KN, Bulik CM. Binge eating disorder treatment: a systematic review of randomized controlled trials. Int J Eat Disord. 2007;40:337–48. [PubMed] [Google Scholar]
16. Womble LG, Williamson DA, Martin CK, Zucker NL, Thaw JM, Netemeyer R, et al. Psychosocial variables associated with binge eating in obese males and females. Int J Eat Disord. 2001;30:217–21. [PubMed] [Google Scholar]
17. Geliebter A, Aversa A. Emotional eating in overweight, normal weight, and underweight individuals. Eat Behav. 2003;3:341–7. [PubMed] [Google Scholar]
18. Steiger H, Gauvin L, Engelberg MJ, Ying Kin NM, Israel M, Wonderlich SA, et al. Mood- and restraint-based antecedents to binge episodes in bulimia nervosa: possible influences of the serotonin system. Psychol Med. 2005;35:1553–62. [PubMed] [Google Scholar]
19. Stice E, Cameron RP, Killen JD, Hayward C, Taylor CB. Naturalistic weight-reduction efforts prospectively predict growth in relative weight and onset of obesity among female adolescents. J Consult Clin Psychol. 1999;67:967–74. [PubMed] [Google Scholar]
20. Drapeau V, Provencher V, Lemieux S, Despres JP, Bouchard C, Tremblay A. Do 6-y changes in eating behaviors predict changes in body weight? Results from the Quebec Family Study. Int J Obes Relat Metab Disord. 2003;27:808–14. [PubMed] [Google Scholar]
21. Greeno CG, Wing RR. Stress-induced eating. Psychol Bull. 1994;115:444–64. [PubMed] [Google Scholar]
22. Heatherton TF, Herman CP, Polivy J. Effects of physical threat and ego threat on eating behavior. J Pers Soc Psychol. 1991;60:138–43. [PubMed] [Google Scholar]
23. Rutledge T, Linden W. To eat or not to eat: affective and physiological mechanisms in the stress-eating relationship. J Behav Med. 1998;21:221–40. [PubMed] [Google Scholar]
24. Chua JL, Touyz S, Hill AJ. Negative mood-induced overeating in obese binge eaters: an experimental study. Int J Obes Relat Metab Disord. 2004;28:606–10. [PubMed] [Google Scholar]
25. Epel E, Lapidus R, McEwen B, Brownell K. Stress may add bite to appetite in women: a laboratory study of stress-induced cortisol and eating behavior. Psychoneuroendocrinology. 2001;26:37–49. [PubMed] [Google Scholar]
26. Fay SH, Finlayson G. Negative affect-induced food intake in non-dieting women is reward driven and associated with restrained-disinhibited eating subtype. Appetite. 2011 [PubMed] [Google Scholar]
27. Sheppard-Sawyer CL, McNally RJ, Fischer JH. Film-induced sadness as a trigger for disinhibited eating. Int J Eat Disord. 2000;28:215–20. [PubMed] [Google Scholar]
28. Yeomans MR, Coughlan E. Mood-induced eating. Interactive effects of restraint and tendency to overeat. Appetite. 2009;52:290–8. [PubMed] [Google Scholar]
29. Elfhag K, Rossner S. Who succeeds in maintaining weight loss? A conceptual review of factors associated with weight loss maintenance and weight regain. Obes Rev. 2005;6:67–85. [PubMed] [Google Scholar]
30. Werrij MQ, Jansen A, Mulkens S, Elgersma HJ, Ament AJ, Hospers HJ. Adding cognitive therapy to dietetic treatment is associated with less relapse in obesity. J Psychosom Res. 2009;67:315–24. [PubMed] [Google Scholar]
31. Allison S, Timmerman GM. Anatomy of a binge: food environment and characteristics of nonpurge binge episodes. Eat Behav. 2007;8:31–8. [PubMed] [Google Scholar]
32. Reid M, Hammersley R. The effects of sucrose and maize oil on subsequent food intake and mood. Br J Nutr. 1999;82:447–55. [PubMed] [Google Scholar]
33. Benton D, Owens D. Is raised blood glucose associated with the relief of tension? J Psychosom Res. 1993;37:723–35. [PubMed] [Google Scholar]
34. Wells AS, Read NW, Laugharne JD, Ahluwalia NS. Alterations in mood after changing to a low-fat diet. Br J Nutr. 1998;79:23–30. [PubMed] [Google Scholar]
35. Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F. Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch Neurol. 2007;64:1575–9. [PubMed] [Google Scholar]
36. Volkow ND, Wang GJ, Fowler JS, Telang F. Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology. Philos Trans R Soc Lond B Biol Sci. 2008;363:3191–200. [PMC free article] [PubMed] [Google Scholar]
37. Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, et al. Brain dopamine and obesity. Lancet. 2001;357:354–7. [PubMed] [Google Scholar]
38. Volkow ND, Wang GJ, Telang F, Fowler JS, Thanos PK, Logan J, et al. Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors. Neuroimage. 2008;42:1537–43. [PMC free article] [PubMed] [Google Scholar]
39. Stice E, Spoor S, Bohon C, Small DM. Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele. Science. 2008;322:449–52. [PMC free article] [PubMed] [Google Scholar]
40. Kaplan AS, Levitan RD, Yilmaz Z, Davis C, Tharmalingam S, Kennedy JL. A DRD4/BDNF gene-gene interaction associated with maximum BMI in women with bulimia nervosa. Int J Eat Disord. 2008;41:22–8.[PubMed] [Google Scholar]
41. Levitan RD, Masellis M, Basile VS, Lam RW, Kaplan AS, Davis C, et al. The dopamine-4 receptor gene associated with binge eating and weight gain in women with seasonal affective disorder: an evolutionary perspective. Biol Psychiatry. 2004;56:665–9. [PubMed] [Google Scholar]
42. Stice E, Yokum S, Blum K, Bohon C. Weight gain is associated with reduced striatal response to palatable food. J Neurosci. 2010;30:13105–9. [PMC free article] [PubMed] [Google Scholar]
43. Steele KE, Prokopowicz GP, Schweitzer MA, Magunsuon TH, Lidor AO, Kuwabawa H, et al. Alterations of central dopamine receptors before and after gastric bypass surgery. Obes Surg. 2010;20:369–74. [PubMed] [Google Scholar]
44. Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Jayne M, et al. Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. J Neurosci. 2007;27:12700–6.[PMC free article] [PubMed] [Google Scholar]
45. Volkow ND, Wang GJ, Maynard L, Jayne M, Fowler JS, Zhu W, et al. Brain dopamine is associated with eating behaviors in humans. Int J Eat Disord. 2003;33:136–42. [PubMed] [Google Scholar]
46. Wang GJ, Geliebter A, Volkow ND, Telang FW, Logan J, Jayne MC, et al. Enhanced Striatal Dopamine Release During Food Stimulation in Binge Eating Disorder. Obesity (Silver Spring) 2011 [PMC free article][PubMed] [Google Scholar]
47. Avena NM, Long KA, Hoebel BG. Sugar-dependent rats show enhanced responding for sugar after abstinence: evidence of a sugar deprivation effect. Physiol Behav. 2005;84:359–62. [PubMed] [Google Scholar]
48. Colantuoni C, Rada P, McCarthy J, Patten C, Avena NM, Chadeayne A, et al. Evidence that intermittent, excessive sugar intake causes endogenous opioid dependence. Obes Res. 2002;10:478–88. [PubMed] [Google Scholar]
49. Avena NM, Bocarsly ME, Rada P, Kim A, Hoebel BG. After daily bingeing on a sucrose solution, food deprivation induces anxiety and accumbens dopamine/acetylcholine imbalance. Physiol Behav. 2008;94:309–15.[PMC free article] [PubMed] [Google Scholar]
50. Rada P, Pothos E, Mark GP, Hoebel BG. Microdialysis evidence that acetylcholine in the nucleus accumbens is involved in morphine withdrawal and its treatment with clonidine. Brain Res. 1991;561:354–6. [PubMed] [Google Scholar]
51. Pothos E, Rada P, Mark GP, Hoebel BG. Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone-precipitated withdrawal and clonidine treatment. Brain Res. 1991;566:348–50.[PubMed] [Google Scholar]
52. Hoebel BG, Avena NM, Rada P. Accumbens dopamine-acetylcholine balance in approach and avoidance. Curr Opin Pharmacol. 2007;7:617–27. [PMC free article] [PubMed] [Google Scholar]
53. Cottone P, Sabino V, Roberto M, Bajo M, Pockros L, Frihauf JB, et al. CRF system recruitment mediates dark side of compulsive eating. Proc Natl Acad Sci U S A. 2009;106:20016–20. [PMC free article] [PubMed] [Google Scholar]
54. Cottone P, Sabino V, Steardo L, Zorrilla EP. Consummatory, anxiety-related and metabolic adaptations in female rats with alternating access to preferred food. Psychoneuroendocrinology. 2009;34:38–49.[PMC free article] [PubMed] [Google Scholar]
55. Merlo Pich E, Lorang M, Yeganeh M, Rodriguez de Fonseca F, Raber J, Koob GF, et al. Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J Neurosci. 1995;15:5439–47.[PMC free article] [PubMed] [Google Scholar]
56. Zorrilla EP, Valdez GR, Weiss F. Changes in levels of regional CRF-like-immunoreactivity and plasma corticosterone during protracted drug withdrawal in dependent rats. Psychopharmacology (Berl) 2001;158:374–81.[PubMed] [Google Scholar]
57. Funk CK, Zorrilla EP, Lee MJ, Rice KC, Koob GF. Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats. Biol Psychiatry. 2007;61:78–86. [PMC free article][PubMed] [Google Scholar]
58. Roberto M, Cruz MT, Gilpin NW, Sabino V, Schweitzer P, Bajo M, et al. Corticotropin releasing factor-induced amygdala gamma-aminobutyric Acid release plays a key role in alcohol dependence. Biol Psychiatry. 2010;67:831–9. [PMC free article] [PubMed] [Google Scholar]
59. Sommer WH, Rimondini R, Hansson AC, Hipskind PA, Gehlert DR, Barr CS, et al. Upregulation of voluntary alcohol intake, behavioral sensitivity to stress, and amygdala crhr1 expression following a history of dependence. Biol Psychiatry. 2008;63:139–45. [PubMed] [Google Scholar]
60. Maj M, Turchan J, Smialowska M, Przewlocka B. Morphine and cocaine influence on CRF biosynthesis in the rat central nucleus of amygdala. Neuropeptides. 2003;37:105–10. [PubMed] [Google Scholar]
61. Weiss F, Ciccocioppo R, Parsons LH, Katner S, Liu X, Zorrilla EP, et al. Compulsive drug-seeking behavior and relapse. Neuroadaptation, stress, and conditioning factors. Ann N Y Acad Sci. 2001;937:1–26. [PubMed] [Google Scholar]
62. McNally GP, Akil H. Role of corticotropin-releasing hormone in the amygdala and bed nucleus of the stria terminalis in the behavioral, pain modulatory, and endocrine consequences of opiate withdrawal. Neuroscience. 2002;112:605–17. [PubMed] [Google Scholar]
63. Heinrichs SC, Menzaghi F, Schulteis G, Koob GF, Stinus L. Suppression of corticotropin-releasing factor in the amygdala attenuates aversive consequences of morphine withdrawal. Behav Pharmacol. 1995;6:74–80. [PubMed] [Google Scholar]
64. Richter RM, Weiss F. In vivo CRF release in rat amygdala is increased during cocaine withdrawal in self-administering rats. Synapse. 1999;32:254–61. [PubMed] [Google Scholar]
65. Rodriguez de Fonseca F, Carrera MR, Navarro M, Koob GF, Weiss F. Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal. Science. 1997;276:2050–4. [PubMed] [Google Scholar]
66. George O, Ghozland S, Azar MR, Cottone P, Zorrilla EP, Parsons LH, et al. CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats. Proc Natl Acad Sci U S A. 2007;104:17198–203. [PMC free article] [PubMed] [Google Scholar]
67. Marcinkiewcz CA, Prado MM, Isaac SK, Marshall A, Rylkova D, Bruijnzeel AW. Corticotropin-releasing factor within the central nucleus of the amygdala and the nucleus accumbens shell mediates the negative affective state of nicotine withdrawal in rats. Neuropsychopharmacology. 2009;34:1743–52. [PMC free article] [PubMed] [Google Scholar]
68. Logrip ML, Koob GF, Zorrilla EP. Role of corticotropin-releasing factor in drug addiction: potential for pharmacological intervention. CNS Drugs. 2011;25:271–87. [PMC free article] [PubMed] [Google Scholar]
69. Martin-Fardon R, Zorrilla EP, Ciccocioppo R, Weiss F. Role of innate and drug-induced dysregulation of brain stress and arousal systems in addiction: Focus on corticotropin-releasing factor, nociceptin/orphanin FQ, and orexin/hypocretin. Brain Res. 2010;1314:145–61. [PMC free article] [PubMed] [Google Scholar]
70. Koob GF, Zorrilla EP. Neurobiological mechanisms of addiction: focus on corticotropin-releasing factor. Curr Opin Investig Drugs. 2010;11:63–71. [PMC free article] [PubMed] [Google Scholar]
71. Knapp DJ, Overstreet DH, Moy SS, Breese GR. SB242084, flumazenil, and CRA1000 block ethanol withdrawal-induced anxiety in rats. Alcohol. 2004;32:101–11. [PMC free article] [PubMed] [Google Scholar]
72. Overstreet DH, Knapp DJ, Breese GR. Modulation of multiple ethanol withdrawal-induced anxiety-like behavior by CRF and CRF1 receptors. Pharmacol Biochem Behav. 2004;77:405–13. [PMC free article] [PubMed] [Google Scholar]
73. Skelton KH, Oren D, Gutman DA, Easterling K, Holtzman SG, Nemeroff CB, et al. The CRF1 receptor antagonist, R121919, attenuates the severity of precipitated morphine withdrawal. Eur J Pharmacol. 2007;571:17–24. [PubMed] [Google Scholar]
74. Stinus L, Cador M, Zorrilla EP, Koob GF. Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats. Neuropsychopharmacology. 2005;30:90–8. [PubMed] [Google Scholar]
75. Skelton KH, Gutman DA, Thrivikraman KV, Nemeroff CB, Owens MJ. The CRF1 receptor antagonist R121919 attenuates the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal. Psychopharmacology (Berl) 2007;192:385–96. [PubMed] [Google Scholar]
76. Sarnyai Z, Biro E, Gardi J, Vecsernyes M, Julesz J, Telegdy G. Brain corticotropin-releasing factor mediates ‘anxiety-like’ behavior induced by cocaine withdrawal in rats. Brain Res. 1995;675:89–97. [PubMed] [Google Scholar]
77. Basso AM, Spina M, Rivier J, Vale W, Koob GF. Corticotropin-releasing factor antagonist attenuates the “anxiogenic-like” effect in the defensive burying paradigm but not in the elevated plus-maze following chronic cocaine in rats. Psychopharmacology (Berl) 1999;145:21–30. [PubMed] [Google Scholar]
78. Valdez GR, Roberts AJ, Chan K, Davis H, Brennan M, Zorrilla EP, et al. Increased ethanol self-administration and anxiety-like behavior during acute ethanol withdrawal and protracted abstinence: regulation by corticotropin-releasing factor. Alcohol Clin Exp Res. 2002;26:1494–501. [PubMed] [Google Scholar]
79. Sabino V, Cottone P, Koob GF, Steardo L, Lee MJ, Rice KC, et al. Dissociation between opioid and CRF1 antagonist sensitive drinking in Sardinian alcohol-preferring rats. Psychopharmacology (Berl) 2006;189:175–86.[PubMed] [Google Scholar]
80. Gilpin NW, Richardson HN, Koob GF. Effects of CRF1-receptor and opioid-receptor antagonists on dependence-induced increases in alcohol drinking by alcohol-preferring (P) rats. Alcohol Clin Exp Res. 2008;32:1535–42. [PMC free article] [PubMed] [Google Scholar]
81. Richardson HN, Zhao Y, Fekete EM, Funk CK, Wirsching P, Janda KD, et al. MPZP: a novel small molecule corticotropin-releasing factor type 1 receptor (CRF1) antagonist. Pharmacol Biochem Behav. 2008;88:497–510.[PMC free article] [PubMed] [Google Scholar]
82. Gehlert DR, Cippitelli A, Thorsell A, Le AD, Hipskind PA, Hamdouchi C, et al. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl- imidazo [1,2-b]pyridazine: a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism. J Neurosci. 2007;27:2718–26. [PMC free article] [PubMed] [Google Scholar]
83. Specio SE, Wee S, O’Dell LE, Boutrel B, Zorrilla EP, Koob GF. CRF(1) receptor antagonists attenuate escalated cocaine self-administration in rats. Psychopharmacology (Berl) 2008;196:473–82. [PMC free article][PubMed] [Google Scholar]
84. Greenwell TN, Funk CK, Cottone P, Richardson HN, Chen SA, Rice KC, et al. Corticotropin-releasing factor-1 receptor antagonists decrease heroin self-administration in long-but not short-access rats. Addict Biol. 2009;14:130–43. [PMC free article] [PubMed] [Google Scholar]
85. Cottone P, Sabino V, Steardo L, Zorrilla EP. Opioid-dependent anticipatory negative contrast and binge-like eating in rats with limited access to highly preferred food. Neuropsychopharmacology. 2008;33:524–35. [PubMed] [Google Scholar]
86. Avena NM, Rada P, Hoebel BG. Sugar and fat bingeing have notable differences in addictive-like behavior. J Nutr. 2009;139:623–8. [PMC free article] [PubMed] [Google Scholar]
87. Wojnicki FH, Charny G, Corwin RL. Binge-type behavior in rats consuming trans-fat-free shortening. Physiol Behav. 2008;94:627–9. [PMC free article] [PubMed] [Google Scholar]
88. Berner LA, Avena NM, Hoebel BG. Bingeing, self-restriction, and increased body weight in rats with limited access to a sweet-fat diet. Obesity (Silver Spring) 2008;16:1998–2002. [PubMed] [Google Scholar]
89. Teegarden SL, Bale TL. Decreases in dietary preference produce increased emotionality and risk for dietary relapse. Biol Psychiatry. 2007;61:1021–9. [PubMed] [Google Scholar]
90. Pickering C, Alsio J, Hulting AL, Schioth HB. Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals. Psychopharmacology (Berl) 2009;204:431–43. [PubMed] [Google Scholar]
91. Johnson PM, Kenny PJ. Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat Neurosci. 2010;13:635–41. [PMC free article] [PubMed] [Google Scholar]
92. Vanderschuren LJ, Everitt BJ. Drug seeking becomes compulsive after prolonged cocaine self-administration. Science. 2004;305:1017–9. [PubMed] [Google Scholar]
93. Dallman MF, Pecoraro N, Akana SF, La Fleur SE, Gomez F, Houshyar H, et al. Chronic stress and obesity: a new view of “comfort food” Proc Natl Acad Sci U S A. 2003;100:11696–701. [PMC free article] [PubMed] [Google Scholar]
94. Ulrich-Lai YM, Christiansen AM, Ostrander MM, Jones AA, Jones KR, Choi DC, et al. Pleasurable behaviors reduce stress via brain reward pathways. Proc Natl Acad Sci U S A. 2010;107:20529–34. [PMC free article][PubMed] [Google Scholar]
95. Christiansen AM, Herman JP, Ulrich-Lai YM. Regulatory interactions of stress and reward on rat forebrain opioidergic and GABAergic circuitry. Stress. 2011;14:205–15. [PMC free article] [PubMed] [Google Scholar]
96. Christiansen AM, Dekloet AD, Ulrich-Lai YM, Herman JP. “Snacking” causes long term attenuation of HPA axis stress responses and enhancement of brain FosB/deltaFosB expression in rats. Physiol Behav. 2011;103:111–6.[PMC free article] [PubMed] [Google Scholar]
97. Ulrich-Lai YM, Ostrander MM, Herman JP. HPA axis dampening by limited sucrose intake: Reward frequency vs. caloric consumption. Physiol Behav. 2011;103:104–10. [PMC free article] [PubMed] [Google Scholar]
98. Maniam J, Morris MJ. Voluntary exercise and palatable high-fat diet both improve behavioural profile and stress responses in male rats exposed to early life stress: role of hippocampus. Psychoneuroendocrinology. 2010;35:1553–64. [PubMed] [Google Scholar]
99. Krolow R, Noschang CG, Arcego D, Andreazza AC, Peres W, Goncalves CA, et al. Consumption of a palatable diet by chronically stressed rats prevents effects on anxiety-like behavior but increases oxidative stress in a sex-specific manner. Appetite. 2010;55:108–16. [PubMed] [Google Scholar]
100. Martin J, Timofeeva E. Intermittent access to sucrose increases sucrose-licking activity and attenuates restraint stress-induced activation of the lateral septum. Am J Physiol Regul Integr Comp Physiol. 2010;298:R1383–98.[PubMed] [Google Scholar]
101. Maniam J, Morris MJ. Palatable cafeteria diet ameliorates anxiety and depression-like symptoms following an adverse early environment. Psychoneuroendocrinology. 2010;35:717–28. [PubMed] [Google Scholar]
102. Maniam J, Morris MJ. Long-term postpartum anxiety and depression-like behavior in mother rats subjected to maternal separation are ameliorated by palatable high fat diet. Behav Brain Res. 2010;208:72–9. [PubMed] [Google Scholar]
103. Davis C, Levitan RD, Carter J, Kaplan AS, Reid C, Curtis C, et al. Personality and eating behaviors: a case-control study of binge eating disorder. Int J Eat Disord. 2008;41:243–50. [PubMed] [Google Scholar]
104. Warne JP. Shaping the stress response: interplay of palatable food choices, glucocorticoids, insulin and abdominal obesity. Mol Cell Endocrinol. 2009;300:137–46. [PubMed] [Google Scholar]
105. Kinzig KP, Hargrave SL, Honors MA. Binge-type eating attenuates corticosterone and hypophagic responses to restraint stress. Physiol Behav. 2008;95:108–13. [PubMed] [Google Scholar]
106. Fachin A, Silva RK, Noschang CG, Pettenuzzo L, Bertinetti L, Billodre MN, et al. Stress effects on rats chronically receiving a highly palatable diet are sex-specific. Appetite. 2008;51:592–8. [PubMed] [Google Scholar]
107. Ulrich-Lai YM, Ostrander MM, Thomas IM, Packard BA, Furay AR, Dolgas CM, et al. Daily limited access to sweetened drink attenuates hypothalamic-pituitary-adrenocortical axis stress responses. Endocrinology. 2007;148:1823–34. [PMC free article] [PubMed] [Google Scholar]
108. Pecoraro N, Reyes F, Gomez F, Bhargava A, Dallman MF. Chronic stress promotes palatable feeding, which reduces signs of stress: feedforward and feedback effects of chronic stress. Endocrinology. 2004;145:3754–62.[PubMed] [Google Scholar]
109. Nanni G, Scheggi S, Leggio B, Grappi S, Masi F, Rauggi R, et al. Acquisition of an appetitive behavior prevents development of stress-induced neurochemical modifications in rat nucleus accumbens. J Neurosci Res. 2003;73:573–80. [PubMed] [Google Scholar]
110. Dallman MF, Pecoraro NC, la Fleur SE. Chronic stress and comfort foods: self-medication and abdominal obesity. Brain Behav Immun. 2005;19:275–80. [PubMed] [Google Scholar]
111. Teegarden SL, Bale TL. Effects of stress on dietary preference and intake are dependent on access and stress sensitivity. Physiol Behav. 2008;93:713–23. [PMC free article] [PubMed] [Google Scholar]
112. Shepard JD, Bossert JM, Liu SY, Shaham Y. The anxiogenic drug yohimbine reinstates methamphetamine seeking in a rat model of drug relapse. Biol Psychiatry. 2004;55:1082–9. [PubMed] [Google Scholar]
113. Le AD, Harding S, Juzytsch W, Funk D, Shaham Y. Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology (Berl) 2005;179:366–73. [PubMed] [Google Scholar]
114. Lee B, Tiefenbacher S, Platt DM, Spealman RD. Pharmacological blockade of alpha2-adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys. Neuropsychopharmacology. 2004;29:686–93.[PubMed] [Google Scholar]
115. Ghitza UE, Gray SM, Epstein DH, Rice KC, Shaham Y. The anxiogenic drug yohimbine reinstates palatable food seeking in a rat relapse model: a role of CRF1 receptors. Neuropsychopharmacology. 2006;31:2188–96.[PMC free article] [PubMed] [Google Scholar]
116. Le AD, Funk D, Juzytsch W, Coen K, Navarre BM, Cifani C, et al. Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats. Psychopharmacology (Berl) 2011[PMC free article] [PubMed] [Google Scholar]
117. Richards JK, Simms JA, Steensland P, Taha SA, Borgland SL, Bonci A, et al. Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats. Psychopharmacology (Berl) 2008;199:109–17. [PMC free article] [PubMed] [Google Scholar]
118. Nair SG, Gray SM, Ghitza UE. Role of food type in yohimbine- and pellet-priming-induced reinstatement of food seeking. Physiol Behav. 2006;88:559–66. [PMC free article] [PubMed] [Google Scholar]
119. Koob GF, Le Moal M. Neurobiology of Addiction. London: Academic Press; 2006. [Google Scholar]
120. Pecina S, Schulkin J, Berridge KC. Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress? BMC Biol. 2006;4(8)[PMC free article] [PubMed] [Google Scholar]
121. Nair SG, Navarre BM, Cifani C, Pickens CL, Bossert JM, Shaham Y. Role of dorsal medial prefrontal cortex dopamine D1-family receptors in relapse to high-fat food seeking induced by the anxiogenic drug yohimbine. Neuropsychopharmacology. 2011;36:497–510. [PMC free article] [PubMed] [Google Scholar]
122. Boggiano MM, Chandler PC. Binge eating in rats produced by combining dieting with stress. Curr Protoc Neurosci. 2006;Chapter 9(Unit9):23A. [PubMed] [Google Scholar]
123. Hagan MM, Wauford PK, Chandler PC, Jarrett LA, Rybak RJ, Blackburn K. A new animal model of binge eating: key synergistic role of past caloric restriction and stress. Physiol Behav. 2002;77:45–54. [PubMed] [Google Scholar]
124. Hagan MM, Chandler PC, Wauford PK, Rybak RJ, Oswald KD. The role of palatable food and hunger as trigger factors in an animal model of stress induced binge eating. Int J Eat Disord. 2003;34:183–97. [PubMed] [Google Scholar]
125. Waters A, Hill A, Waller G. Internal and external antecedents of binge eating episodes in a group of women with bulimia nervosa. Int J Eat Disord. 2001;29:17–22. [PubMed] [Google Scholar]
126. Cifani C, Polidori C, Melotto S, Ciccocioppo R, Massi M. A preclinical model of binge eating elicited by yo-yo dieting and stressful exposure to food: effect of sibutramine, fluoxetine, topiramate, and midazolam. Psychopharmacology (Berl) 2009;204:113–25. [PubMed] [Google Scholar]
127. Boggiano MM, Chandler PC, Viana JB, Oswald KD, Maldonado CR, Wauford PK. Combined dieting and stress evoke exaggerated responses to opioids in binge-eating rats. Behav Neurosci. 2005;119:1207–14. [PubMed] [Google Scholar]
128. Colantuoni C, Schwenker J, McCarthy J, Rada P, Ladenheim B, Cadet JL, et al. Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain. Neuroreport. 2001;12:3549–52. [PubMed] [Google Scholar]
129. Bello NT, Guarda AS, Terrillion CE, Redgrave GW, Coughlin JW, Moran TH. Repeated binge access to a palatable food alters feeding behavior, hormone profile, and hindbrain c-Fos responses to a test meal in adult male rats. Am J Physiol Regul Integr Comp Physiol. 2009;297:R622–31. [PMC free article] [PubMed] [Google Scholar]
130. Cooper SJ. Palatability-dependent appetite and benzodiazepines: new directions from the pharmacology of GABA(A) receptor subtypes. Appetite. 2005;44:133–50. [PubMed] [Google Scholar]
131. Bruijnzeel AW, Prado M, Isaac S. Corticotropin-releasing factor-1 receptor activation mediates nicotine withdrawal-induced deficit in brain reward function and stress-induced relapse. Biol Psychiatry. 2009;66:110–7.[PMC free article] [PubMed] [Google Scholar]
132. Geiger BM, Haburcak M, Avena NM, Moyer MC, Hoebel BG, Pothos EN. Deficits of mesolimbic dopamine neurotransmission in rat dietary obesity. Neuroscience. 2009;159:1193–9. [PMC free article] [PubMed] [Google Scholar]
133. Rada P, Avena NM, Hoebel BG. Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell. Neuroscience. 2005;134:737–44. [PubMed] [Google Scholar]
134. Bello NT, Lucas LR, Hajnal A. Repeated sucrose access influences dopamine D2 receptor density in the striatum. Neuroreport. 2002;13:1575–8. [PMC free article] [PubMed] [Google Scholar]
135. Spangler R, Wittkowski KM, Goddard NL, Avena NM, Hoebel BG, Leibowitz SF. Opiate-like effects of sugar on gene expression in reward areas of the rat brain. Brain Res Mol Brain Res. 2004;124:134–42. [PubMed] [Google Scholar]
136. Bello NT, Sweigart KL, Lakoski JM, Norgren R, Hajnal A. Restricted feeding with scheduled sucrose access results in an upregulation of the rat dopamine transporter. Am J Physiol Regul Integr Comp Physiol. 2003;284:R1260–8. [PubMed] [Google Scholar]
137. Rada P, Bocarsly ME, Barson JR, Hoebel BG, Leibowitz SF. Reduced accumbens dopamine in Sprague-Dawley rats prone to overeating a fat-rich diet. Physiol Behav. 2010;101:394–400. [PMC free article] [PubMed] [Google Scholar]
138. Thanos PK, Michaelides M, Piyis YK, Wang GJ, Volkow ND. Food restriction markedly increases dopamine D2 receptor (D2R) in a rat model of obesity as assessed with in-vivo muPET imaging ([11C] raclopride) and in-vitro ([3H] spiperone) autoradiography. Synapse. 2008;62:50–61. [PubMed] [Google Scholar]
Public domain information on the National Library of Medicine (NLM) Web pages may be freely distributed and copied.
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3304465/