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The Neurobiological Underpinnings of Obesity and Binge Eating: A Rationale for Adopting the Food Addiction Model

  • Dana G. Smith
    Correspondence
    Address correspondence to Dana G. Smith, B.A., University of Cambridge Behavioural and Clinical Neuroscience Institute, Department of Psychology, Downing Street, Cambridge CB2 3EB, United Kingdom
    Affiliations
    Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, United Kingdom
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  • Trevor W. Robbins
    Affiliations
    Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, United Kingdom
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      The food addiction model of overeating has been proposed to help explain the widespread advancement of obesity over the last 30 years. Parallels in neural substrates and neurochemistry, as well as corresponding motivational and behavioral traits, are increasingly coming to light; however, there are still key differences between the two disorders that must be acknowledged. We critically examine these common and divergent characteristics using the theoretical framework of prominent drug addiction models, investigating the neurobiological underpinnings of both behaviors in an attempt to justify whether classification of obesity and binge eating as an addictive disorder is merited.

      Key Words

      There has been a surge in waistlines and weight gain around the world over the last 30 years, with up to two thirds of the population of some western nations classified as overweight or obese. Obesity-related maladies, such as type II diabetes, hypertension, and liver disease, have replaced smoking as the leading cause of preventable death in adults, reducing life expectancy by an estimated 6 to 7 years (
      • Jia H.
      • Lubetkin E.I.
      Trends in quality-adjusted life-years lost contributed by smoking and obesity.
      ,
      • Haslam D.W.
      • James W.P.
      Obesity.
      ). The health and science communities have responded to this epidemic by working to discover the physiological and psychological underpinnings of obesity and excessive food consumption, in the hopes of understanding the multitude of factors that have contributed to our present state.
      One plausible motivational approach is that overeating reflects an addiction analogous to drug abuse, with individuals becoming physically and psychologically dependent on foods high in fat and sugar. The case for classifying overeating as an addictive disorder is particularly strong in instances of binge eating, defined as “recurring episodes of eating, in a discrete period of time, an amount of food that is definitely larger than most people would eat during a similar period of time [with a]…lack of control during the episodes” (

      American Psychiatric Association (2000): Diagnostic and Statistical Manual of Mental Disorders, 4th ed Washington, DC: American Psychiatric Association

      ). These criteria closely match those used to describe drug dependence (Table 1), and binge eating is currently being considered for classification as an addiction spectrum disorder in the upcoming DSM-V (www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=372#). Specifically, addicted individuals experience a lack of control in the face of food or drugs of abuse; have a continuation of overuse despite severe health, social, legal, and financial problems; and are unsuccessful at attempts to cut back or reduce their consumption. These behaviors are typically accompanied by feelings of guilt, remorse, and distress.
      Table 1DSM-IV-TR Definitions of Substance Dependence and Binge Eating Disorder
      Comorbid SymptomSubstance DependenceBinge Eating Disorder
      Escalation of UseThe substance is taken in larger amounts or over a longer period than intended.Eating large amounts of food when not feeling physically hungry.
      Loss of ControlThere is a persistent desire or unsuccessful effort to cut down or control substance use.A sense of lack of control during the episodes, e.g., a feeling that one can’t stop eating or control what or how much one is eating.
      Social ConsequencesImportant social, occupational, or recreational activities are given up or reduced because of use.Eating alone because of being embarrassed by how much one is eating.
      Personal DistressThe substance use is continued despite knowledge of having a persistent physical or psychological problem that is likely to have been caused or exacerbated by the substance.Feeling disgusted with oneself, depressed, or feeling very guilty after overeating; marked distress regarding binge eating; eating until feeling uncomfortably full.
      A categorical comparison of the DSM-IV-TR definitions of substance dependence and binge eating criteria for both bulimia nervosa and binge eating disorder (3).
      In addition to analogous behavioral traits, there are also similarities in the brain structure and neurochemical profile of substance-dependent and obese individuals. These include abnormalities in the dopamine and opioid neurotransmitter systems, changes in fronto-striatal circuitry, and associated dysfunctional impulsive and compulsive behaviors. Individuals at risk for developing drug or food dependency show a decrease in striatal dopamine D2 receptor availability, potentially making them more vulnerable to the rewarding properties of pleasurable stimuli (
      • Wang G.J.
      • Volkow N.D.
      • Thanos P.K.
      • Fowler J.S.
      Similarity between obesity and drug addiction as assessed by neurofunctional imaging: A concept review.
      ). Highly palatable food and drugs of abuse directly affect the mesolimbic dopamine and opioid pathways, with consumption of each type of substance increasing neurotransmitter levels (
      • Small D.M.
      • Jones-Gotman M.
      • Dagher A.
      Feeding-induced dopamine release in dorsal striatum correlates with meal pleasantness ratings in healthy human volunteers.
      ,
      • Dichiara G.
      • Imperato A.
      Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.
      ,
      • Rada P.
      • Avena N.M.
      • Hoebel B.G.
      Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell.
      ). Additionally, cue-induced anticipation of these substances can elevate activity in the fronto-limbic circuitry, thought to correspond with striatal dopamine release (
      • Small D.M.
      • Jones-Gotman M.
      • Dagher A.
      Feeding-induced dopamine release in dorsal striatum correlates with meal pleasantness ratings in healthy human volunteers.
      ,
      • Pelchat M.L.
      • Johnson A.
      • Chan R.
      • Valdez J.
      • Ragland J.D.
      Images of desire: Food-craving activation during fMRI.
      ,
      • O'Doherty J.P.
      • Deichmann R.
      • Critchley H.D.
      • Dolan R.J.
      Neural responses during anticipation of a primary taste reward.
      ,
      • Stice E.
      • Spoor S.
      • Bohon C.
      • Veldhuizen M.G.
      • Small D.M.
      Relation of reward from food intake and anticipated food intake to obesity: A functional magnetic resonance imaging study.
      ). The reward deficiency hypothesis has been advanced to explain how a baseline hypofunctioning dopamine system might lead to compulsive consumption of drugs of abuse, as individuals attempt to self-medicate via direct manipulation of neurotransmitter levels (
      • Blum K.
      • Braverman E.R.
      • Holder J.M.
      • Lubar J.F.
      • Monastra V.J.
      • Miller D.
      • et al.
      Reward deficiency syndrome: A biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors.
      ). This theory has also been proposed for obese individuals, similarly self-medicating flattened baseline dopamine functioning by overconsumption of high-fat/high-sugar foods (
      • Blum K.
      • Braverman E.R.
      • Holder J.M.
      • Lubar J.F.
      • Monastra V.J.
      • Miller D.
      • et al.
      Reward deficiency syndrome: A biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors.
      ,
      • Davis C.
      • Carter J.C.
      Compulsive overeating as an addiction disorder. A review of theory and evidence.
      ).
      This review will investigate the neurobiological underpinnings of obesity and binge eating, taking direction from drug addiction literature, as a rationale for adopting a food addiction model. While this idea has been proposed previously, this review will synthesize the work from several labs in the fields of drug addiction and obesity in an attempt to provide a new perspective on the issue. We will incorporate in one comprehensive survey data from both preclinical and human research and will use the theoretical framework of prominent drug addiction hypotheses over the last 40 years to structure and direct the argument. We will discuss common and divergent neural substrates, neurochemistry, and behavioral characteristics existing between the two conditions in an attempt to justify classification as an addictive disorder.

      Opponent-Process Theory: A Binge-Eating Model of Food Addiction

      Withdrawal is one of the primary instigators of relapse in drug-dependent individuals, particularly opiate users, negatively reinforcing drug administration in an opponent-process model (
      • Solomon R.L.
      The opponent-process theory of acquired motivation: The costs of pleasure and the benefits of pain.
      ,
      • Wikler A.
      • Pescor F.T.
      Classical conditioning of a morphine abstinence phenomenon, reinforcement of opioid-drinking behavior and "relapse" in morphine-addicted rats.
      ). Positive reinforcers that produce affective or hedonic experiences are followed by disparate processes producing contrasting negative effects in a simple dynamic control system (
      • Solomon R.L.
      The opponent-process theory of acquired motivation: The costs of pleasure and the benefits of pain.
      ). These withdrawal symptoms typically manifest as opposing physiological and psychological reactions to those experienced during the initial high, motivating drug users to take more of the drug to alleviate the unpleasant symptoms. Withdrawal can be initiated through drug deprivation or administration of opioid receptor antagonists, systemically or into the striatum (
      • Bozarth M.A.
      • Wise R.A.
      Anatomically distinct opiate receptor fields mediate reward and physical dependence.
      ). Both manipulations result in a depletion of dopamine and an upregulation of acetylcholine in the nucleus accumbens, resulting in shivering, sweating, vomiting, anhedonia, and negative affect (
      • Koob G.F.
      • Le Moal M.
      Neurobiology of Addiction.
      ). In rodents, withdrawal symptoms present as anxiety, behavioral depression, and somatic responses such as tremor, teeth chattering, and head shaking.
      Similar to opiate dependence, rats raised on a binge model of sucrose consumption show withdrawal-like symptoms when sucrose access is removed or after administration of an opioid antagonist (
      • Avena N.M.
      • Bocarsly M.E.
      • Rada P.
      • Kim A.
      • Hoebel B.G.
      After daily bingeing on a sucrose solution, food deprivation induces anxiety and accumbens dopamine/acetylcholine imbalance.
      ,
      • Avena N.M.
      • Rada P.
      • Hoebel B.G.
      Evidence for sugar addiction: Behavioral and neurochemical effects of intermittent, excessive sugar intake.
      ,
      • Colantuoni C.
      • Rada P.
      • McCarthy J.
      • Patten C.
      • Avena N.M.
      • Chadeayne A.
      • Hoebel B.G.
      Evidence that intermittent, excessive sugar intake causes endogenous opioid dependence.
      ,
      • Cottone P.
      • Sabino V.
      • Steardo L.
      • Zorrilla E.P.
      Opioid-dependent anticipatory negative contrast and binge-like eating in rats with limited access to highly preferred food.
      ). Following a 12-hour intermittent food deprivation availability cycle, Avena, Hoebel, and colleagues (
      • Ifland J.R.
      • Preuss H.G.
      • Marcus M.T.
      • Rourke K.M.
      • Taylor W.C.
      • Burau K.
      • et al.
      Refined food addiction: A classic substance use disorder.
      ) were able to initiate binge-like tendencies for a high-sucrose solution in rats. Self-administration of food or drugs in a binge manner is consistent with the behavior of dependent users, who take copious amounts when the drug is first available and sporadically increase their dosage as tolerance builds. When highly palatable food is intermittently made available, particularly following a fast, animals display similar tendencies, consuming up to 58% of their daily calories within the first hour of access (
      • Avena N.M.
      • Rada P.
      • Hoebel B.G.
      Evidence for sugar addiction: Behavioral and neurochemical effects of intermittent, excessive sugar intake.
      ,
      • Berner L.A.
      • Avena N.M.
      • Hoebel B.G.
      Bingeing, self-restriction, and increased body weight in rats with limited access to a sweet-fat diet.
      ). These behaviors are in contrast to animals to which sucrose and food chow have been made readily available, suggesting it is the intermittent access and fast-feast model that prompts the binges. After several weeks of these consummatory patterns, bingeing rats display evidence of withdrawal, suggesting physical dependence has developed via changes in neurotransmitter systems, similar to drugs of abuse. While physical withdrawal symptoms from highly palatable foods have not been reported in humans, dysphoria has been anecdotally described after removing sugar from the diet, potentially indicating psychological withdrawal (
      • Ifland J.R.
      • Preuss H.G.
      • Marcus M.T.
      • Rourke K.M.
      • Taylor W.C.
      • Burau K.
      • et al.
      Refined food addiction: A classic substance use disorder.
      ). The overlap of psychological symptoms in humans is notable, suggesting a common pathway involving affect and motivation in food and drugs of abuse. However, physical withdrawal presents only with opiate use, indicating an additional effect from the more potent direct manipulation of the opioid system, likely acting on autonomic pathways (
      • Koob G.F.
      • Le Moal M.
      Drug abuse: Hedonic homeostatic dysregulation.
      ). Elucidating the distinction between physiological and psychological withdrawal could be a target for future research, parsing out possible underlying differences in these affective and autonomic opioid pathways and the unique effects that food and drugs of abuse have on them.
      Craving for drugs is another common contributor to relapse, causing individuals to seek drugs despite a goal to remain abstinent. In animal models, drug seeking is demonstrated via compulsive lever pressing to obtain the substance, despite attempts at extinction and devaluation of the behavior through aversive consequences (
      • Vanderschuren L.J.
      • Everitt B.J.
      Behavioral and neural mechanisms of compulsive drug seeking.
      ,
      • Belin D.
      • Mar A.C.
      • Dalley J.W.
      • Robbins T.W.
      • Everitt B.J.
      High impulsivity predicts the switch to compulsive cocaine-taking.
      ). Analogous tendencies have been demonstrated in response to sugar removal in rats, with enhanced motivation to obtain a sucrose solution after a period of abstinence (
      • Avena N.M.
      • Long K.A.
      • Hoebel B.G.
      Sugar-dependent rats show enhanced responding for sugar after abstinence: Evidence of a sugar deprivation effect.
      ). Similar experiences of craving, particularly for carbohydrates, are reported in human dieting literature (
      • Ifland J.R.
      • Preuss H.G.
      • Marcus M.T.
      • Rourke K.M.
      • Taylor W.C.
      • Burau K.
      • et al.
      Refined food addiction: A classic substance use disorder.
      ). Former opiate-dependent individuals also often report cravings and binges on sweets, as well as food-hoarding behaviors (
      • Cowan J.
      • Devine C.
      Food, eating, and weight concerns of men in recovery from substance addiction.
      ,
      • Morabia A.
      • Fabre J.
      • Chee E.
      • Zeger S.
      • Orsat E.
      • Robert A.
      Diet and opiate addiction: A quantitative assessment of the diet of non-institutionalized opiate addicts.
      ).
      This cross-substitutability of preference is also seen between highly palatable foods and stimulant drugs (
      • Avena N.M.
      • Rada P.
      • Hoebel B.G.
      Evidence for sugar addiction: Behavioral and neurochemical effects of intermittent, excessive sugar intake.
      ). Known as consummatory cross-sensitization, or the gateway effect, prolonged intake and sensitization with one substance can lead to increased consumption of another. For example, animals that preferred the taste of sucrose exhibited greater self-administration of cocaine (
      • Carroll M.E.
      • Anderson M.M.
      • Morgan A.D.
      Regulation of intravenous cocaine self-administration in rats selectively bred for high (HiS) and low (LoS) saccharin intake.
      ). This could be due to an overall greater preference for hedonic substances or could stem from a hypothetical sensitizing or priming effect on shared receptors.

      Opioid System Involvement in Drug and Food Addiction

      Opioid pathways are crucially implicated in the hedonic properties of pleasurable stimuli (
      • Kelley A.E.
      • Bakshi V.P.
      • Haber S.N.
      • Steininger T.L.
      • Will M.J.
      • Zhang M.
      Opioid modulation of taste hedonics within the ventral striatum.
      ), and both endogenous analgesics and synthetic opiate-based drugs have a long history of abuse due to their euphoria-inducing properties. The rewarding effects of opioids are thought to stem both from their direct activation of the opioid system in the striatum, as well as an indirect excitation of the mesolimbic dopamine pathway via gamma-aminobutyric acid receptor inhibition (
      • Kelley A.E.
      • Bakshi V.P.
      • Haber S.N.
      • Steininger T.L.
      • Will M.J.
      • Zhang M.
      Opioid modulation of taste hedonics within the ventral striatum.
      ,
      • Volkow N.D.
      • Wise R.A.
      How can drug addiction help us understand obesity?.
      ). The dopamine and opioid systems can therefore work in tandem to reinforce the pleasurable and rewarding properties of a stimulus.
      Opioids are also implicated in eating, particularly of palatable foods (see [
      • Kelley A.E.
      • Bakshi V.P.
      • Haber S.N.
      • Steininger T.L.
      • Will M.J.
      • Zhang M.
      Opioid modulation of taste hedonics within the ventral striatum.
      ,
      • Berridge K.C.
      Food reward: Brain substrates of wanting and liking.
      ] for review), and injection of opioid agonists into the striatum increases preferential intake of high-fat/high-sugar items, even in previously sated animals (
      • Bakshi V.P.
      • Kelley A.E.
      Feeding induced by opioid stimulation of the ventral striatum: Role of opiate receptor subtypes.
      ,
      • Zhang M.
      • Gosnell B.A.
      • Kelley A.E.
      Intake of high-fat food is selectively enhanced by mu opioid receptor stimulation within the nucleus accumbens.
      ). Opioid agonists increase pleasurable taste reactivity (
      • Berridge K.C.
      Food reward: Brain substrates of wanting and liking.
      ,
      • Doyle T.G.
      • Berridge K.C.
      • Gosnell B.A.
      Morphine enhances hedonic taste palatability in rats.
      ), as well as willingness to work for a food reward, increasing the breakpoint in a progressive ratio schedule (
      • Kelley A.E.
      • Bakshi V.P.
      • Haber S.N.
      • Steininger T.L.
      • Will M.J.
      • Zhang M.
      Opioid modulation of taste hedonics within the ventral striatum.
      ,
      • Zhang M.
      • Balmadrid C.
      • Kelley A.E.
      Nucleus accumbens opioid, GABaergic, and dopaminergic modulation of palatable food motivation: Contrasting effects revealed by a progressive ratio study in the rat.
      ). Conversely, opioid receptor antagonists will selectively reduce ingestion of high-fat/high-sugar items (
      • Cottone P.
      • Sabino V.
      • Steardo L.
      • Zorrilla E.P.
      Opioid-dependent anticipatory negative contrast and binge-like eating in rats with limited access to highly preferred food.
      ,
      • Drewnowski A.
      • Krahn D.D.
      • Demitrack M.A.
      • Nairn K.
      • Gosnell B.A.
      Taste responses and preferences for sweet high-fat foods: Evidence for opioid involvement.
      ,
      • Apfelbaum M.
      • Mandenoff A.
      Naltrexone suppresses hyperphagia induced in the rat by a highly palatable diet.
      ) and self-report pleasantness ratings (
      • Drewnowski A.
      • Krahn D.D.
      • Demitrack M.A.
      • Nairn K.
      • Gosnell B.A.
      Taste responses and preferences for sweet high-fat foods: Evidence for opioid involvement.
      ,
      • Yeomans M.R.
      • Gray R.W.
      Selective effects of naltrexone on food pleasantness and intake.
      ). As such, opioid receptor antagonists, currently used to treat opiate and alcohol dependency, can decrease food consumption, particularly during a binge, and are suggested as possible treatments for overeating (
      • Rabiner E.A.
      • Beaver J.
      • Makwana A.
      • Searle G.
      • Long C.
      • Nathan P.J.
      • et al.
      Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans.
      ). Intake of palatable foods can also directly increase endorphin release in the hypothalamus, as well as gene expression involving the opioid peptide enkephalin in the striatum (
      • Kelley A.E.
      • Will M.J.
      • Steininger T.L.
      • Zhang M.
      • Haber S.N.
      Restricted daily consumption of a highly palatable food (chocolate Ensure(R)) alters striatal enkephalin gene expression.
      ). This modulation of the opioid system from high-fat/high-sugar consumption is believed to underlie the anecdotal reports of sugar binges and craving in former opiate-dependent individuals (
      • Cowan J.
      • Devine C.
      Food, eating, and weight concerns of men in recovery from substance addiction.
      ,
      • Morabia A.
      • Fabre J.
      • Chee E.
      • Zeger S.
      • Orsat E.
      • Robert A.
      Diet and opiate addiction: A quantitative assessment of the diet of non-institutionalized opiate addicts.
      ).

      Dopamine System Involvement in Appetitive and Consummatory Behaviors

      Delving further into the neurochemical structures involved in addiction, the mesolimbic dopamine system has long been implicated in reward-related responding (
      • Baldo B.A.
      • Kelley A.E.
      Discrete neurochemical coding of distinguishable motivational processes: Insights from nucleus accumbens control of feeding.
      ,
      • Wise R.A.
      Dopamine, learning and motivation.
      ,
      • Wise R.A.
      • Spindler J.
      • deWit H.
      • Gerberg G.J.
      Neuroleptic-induced "anhedonia" in rats: Pimozide blocks reward quality of food.
      ). Briefly, dopaminergic activity is believed to underlie the positive reinforcing properties of both intrinsically rewarding and conditioned stimuli (
      • Wise R.A.
      Dopamine, learning and motivation.
      ). Dopamine agonists increase responding with conditioned reinforcement (
      • Taylor J.R.
      • Robbins T.W.
      6-Hydroxydopamine lesions of the nucleus accumbens, but not of the caudate nucleus, attenuate enhanced responding with reward-related stimuli produced by intra-accumbens d-amphetamine.
      ) and enhance Pavlovian-instrumental transfer (
      • Wyvell C.L.
      • Berridge K.C.
      Incentive sensitization by previous amphetamine exposure: Increased cue-triggered "wanting" for sucrose reward.
      ) and certain forms of conditioning (
      • Wise R.A.
      Dopamine, learning and motivation.
      ). Conversely, dopamine antagonists diminish incentive-motivation and may impede conditioning (
      • Wise R.A.
      Dopamine, learning and motivation.
      ,
      • Wise R.A.
      • Spindler J.
      • deWit H.
      • Gerberg G.J.
      Neuroleptic-induced "anhedonia" in rats: Pimozide blocks reward quality of food.
      ,
      • Koob G.F.
      • Le Moal M.
      Drug addiction, dysregulation of reward, and allostasis.
      ).
      Drugs of abuse directly affect this system, artificially elevating dopamine levels in the striatum and creating associations between drug cues and the feeling of high experienced upon administration. This enhances the substance’s abuse potential, magnifying its rewarding qualities and reinforcing relevant stimulus-reward associations, such that the anticipation of receiving the drug will cause similar increases in dopamine release, even before the drug’s excitatory properties are experienced (
      • Koob G.F.
      • Le Moal M.
      Drug addiction, dysregulation of reward, and allostasis.
      ). Foods high in fat or sugar can have similar effects on the dopamine system, causing a release into the striatum and enhancing behavior associated with reward.
      However, the overall contribution of dopamine to eating and food-related appetitive behaviors is less clear than its role in drug-related reward responding, and the manipulation of food consumption by dopamine release is highly dependent on the site and dose administered. For example, when administered systemically or injected into the nucleus accumbens, low doses of dopamine receptor antagonists can prolong or escalate food consumption (
      • Baldo B.A.
      • Sadeghian K.
      • Basso A.M.
      • Kelley A.E.
      Effects of selective dopamine D1 or D2 receptor blockade within nucleus accumbens subregions on ingestive behavior and associated motor activity.
      ,
      • Clifton P.G.
      • Rusk I.N.
      • Cooper S.J.
      Effects of dopamine D1 and dopamine D2 antagonists on the free feeding and drinking patterns of rats.
      ). These effects are potentially due to dopamine’s direct influence on eating behavior, modulating activation in the ventromedial hypothalamus and affecting the release of neurochemicals implicated in hunger and satiety (
      • Meguid M.M.
      • Fetissov S.O.
      • Blaha V.
      • Yang Z.J.
      Dopamine and serotonin VMN release is related to feeding status in obese and lean Zucker rats.
      ). These include neuropeptide Y and pro-opiomelanocortin, the release of which are inhibited by dopamine receptor agonists, thereby decreasing food intake (
      • Wang G.J.
      • Volkow N.D.
      • Thanos P.K.
      • Fowler J.S.
      Similarity between obesity and drug addiction as assessed by neurofunctional imaging: A concept review.
      ). However, high doses of dopamine receptor antagonists can also inhibit initiation of feeding and decrease food intake (
      • Clifton P.G.
      • Rusk I.N.
      • Cooper S.J.
      Effects of dopamine D1 and dopamine D2 antagonists on the free feeding and drinking patterns of rats.
      ). This may be attributed to dopamine’s motivational effects, the receptor antagonists interfering with learned appetitive responses required to obtain food reward—i.e., rats will still eat to satiation on a dopamine antagonist if the food is readily available but will not work via lever presses to gain access (
      • Baldo B.A.
      • Kelley A.E.
      Discrete neurochemical coding of distinguishable motivational processes: Insights from nucleus accumbens control of feeding.
      ). Conversely, dopamine receptor agonists will increase initiation of behavior and overall responding but typically have an anorectic effect on food consumption (
      • Bakshi V.P.
      • Kelley A.E.
      Dopaminergic regulation of feeding-behavior .2. Differential-effects of amphetamine microinfusion into 3 striatal subregions.
      ). However, it should be noted that microinjections of amphetamine into the striatum have also been seen to increase feeding in some instances (
      • Colle L.M.
      • Wise R.A.
      Facilitory and inhibitory effects of nucleus accumbens amphetamine on feeding.
      ). Thus, there appears to be a dissociation between the role of dopamine in appetitive motivation and consummatory feeding behaviors, though these effects can be site- and dose-dependent (
      • Baldo B.A.
      • Kelley A.E.
      Discrete neurochemical coding of distinguishable motivational processes: Insights from nucleus accumbens control of feeding.
      ).

      Striatal Dopamine System in Addiction Disorders

      A decrease in D2 receptor availability in the striatum is frequently cited in drug addiction literature as a risk factor for stimulant dependence, increasing impulsivity and placing individuals at a greater susceptibility to drugs’ rewarding properties (
      • Volkow N.D.
      • Fowler J.S.
      • Wang G.J.
      • Hitzemann R.
      • Logan J.
      • Schlyer D.J.
      • et al.
      Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers.
      ,
      • Volkow N.D.
      • Wang G.J.
      • Fowler J.S.
      • Gatley S.J.
      • Ding Y.S.
      • Logan J.
      • et al.
      Relationship between psychostimulant-induced "high" and dopamine transporter occupancy.
      ,
      • Volkow N.D.
      • Chang L.
      • Wang G.J.
      • Fowler J.S.
      • Ding Y.S.
      • Sedler M.
      • et al.
      Low level of brain dopamine D2 receptors in methamphetamine abusers: Association with metabolism in the orbitofrontal cortex.
      ). Diminished dopamine release in the nucleus accumbens in response to methylphenidate has been seen in cocaine-dependent individuals as compared with healthy control subjects, providing evidence of further dopamine dysfunction in drug-dependent individuals (
      • Volkow N.D.
      • Wang G.J.
      • Fowler J.S.
      • Logan J.
      • Gatley S.J.
      • Hitzemann R.
      • et al.
      Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects.
      ,
      • Volkow N.D.
      • Wang G.J.
      • Telang F.
      • Fowler J.S.
      • Logan J.
      • Jayne M.
      • et al.
      Profound decreases in dopamine release in striatum in detoxified alcoholics: Possible orbitofrontal involvement.
      ). Conversely, an increase in striatal D2 receptor availability can lead to a decrease in alcohol intake, and individuals with higher endogenous dopamine levels find stimulant drugs less pleasurable than those without (
      • Thanos P.K.
      • Volkow N.D.
      • Freimuth P.
      • Umegaki H.
      • Ikari H.
      • Roth G.
      • et al.
      Overexpression of dopamine D2 receptors reduces alcohol self-administration.
      ,
      • Volkow N.D.
      • Wang G.J.
      • Fowler J.S.
      • Logan J.
      • Gatley S.J.
      • Gifford A.
      • et al.
      Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels.
      ).
      This decrease in D2 receptor availability is further linked to a reduction in orbitofrontal cortex (OFC) metabolism in chronic drug users (
      • Volkow N.D.
      • Fowler J.S.
      • Wang G.J.
      • Hitzemann R.
      • Logan J.
      • Schlyer D.J.
      • et al.
      Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers.
      ,
      • Volkow N.D.
      • Chang L.
      • Wang G.J.
      • Fowler J.S.
      • Ding Y.S.
      • Sedler M.
      • et al.
      Low level of brain dopamine D2 receptors in methamphetamine abusers: Association with metabolism in the orbitofrontal cortex.
      ). This suggests an important feedback loop between the striatum and prefrontal cortex, potentially modulated by dopamine and malfunctioning in stimulant-dependent individuals. Prefrontal cortex involvement in self-control and impulsivity, traits notably diminished in dependent drug users, as well as goal representation, make this dysfunction especially significant. However, it is unknown whether these cortical and subcortical pathologies predate heavy drug use or are a result of the neurotoxic effect of drugs on the brain.
      Decreases in striatal D2 receptors are similarly mirrored in morbidly obese individuals, with receptor availability negatively correlated with body mass index (BMI) (
      • Wang G.J.
      • Volkow N.D.
      • Thanos P.K.
      • Fowler J.S.
      Similarity between obesity and drug addiction as assessed by neurofunctional imaging: A concept review.
      ,
      • Wang G.J.
      • Volkow N.D.
      • Logan J.
      • Pappas N.R.
      • Wong C.T.
      • Zhu W.
      • et al.
      Brain dopamine and obesity.
      ). A decrease in dopamine receptor availability in the hypothalamic pathway has also been linked to an increase in food intake and weight gain in genetic ob/ob obese mice (
      • Pijl H.
      Reduced dopaminergic tone in hypothalamic neural circuits: Expression of a "thrifty" genotype underlying the metabolic syndrome?.
      ). However, treatment with a dopamine receptor agonist led to weight loss in these animals, mimicking the anorectic effects these drugs can have in humans (
      • Pijl H.
      Reduced dopaminergic tone in hypothalamic neural circuits: Expression of a "thrifty" genotype underlying the metabolic syndrome?.
      ). Furthermore, prolonged exposure to both highly palatable foods and stimulant drugs can cause an additional downregulation and decrease in striatal dopamine receptor sensitivity (
      • Volkow N.D.
      • Wang G.J.
      • Fowler J.S.
      • Logan J.
      • Gatley S.J.
      • Hitzemann R.
      • et al.
      Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects.
      ,
      • Bello N.T.
      • Lucas L.R.
      • Hajnal A.
      Repeated sucrose access influences dopamine D2 receptor density in the striatum.
      ).

      Genetic Involvement in Addictive Behaviors

      Much of these findings appear to be modified by a genetic profile affecting dopamine pathways, placing individuals at greater susceptibility for reward system dysfunction. Due to its role in dopamine receptor availability, the A1 allele of the Taq1A gene has been a target for drug and alcohol research over the last 20 years (
      • Noble E.P.
      Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: A review.
      ) and more recently in hyperphagia leading to obesity (
      • Noble E.P.
      Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: A review.
      ,
      • Spitz M.R.
      • Detry M.A.
      • Pillow P.
      • Hu Y.H.
      • Amos C.I.
      • Hong W.K.
      • et al.
      Variant alleles of the D2 dopamine receptor gene and obesity.
      ,
      • Comings D.E.
      • Muhleman D.
      • Ahn C.
      • Gysin R.
      • Flanagan S.D.
      The dopamine-D(2) receptor gene: A genetic risk factor in substance-abuse.
      ). Presence of the A1 allele can cause a 30% to 40% reduction in striatal D2 receptors (
      • Jonsson E.G.
      • Nothen M.M.
      • Grunhage F.
      • Farde L.
      • Nakashima Y.
      • Propping P.
      • Sedvall G.C.
      Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers.
      ) and has been implicated in corresponding deficits in glucose metabolism in the OFC, frontal and temporal gyri, insula, hippocampus, and dorsal and ventral striatum (
      • Noble E.P.
      • Gottschalk L.A.
      • Fallon J.H.
      • Ritchie T.L.
      • Wu J.C.
      D2 dopamine receptor polymorphism and brain regional glucose metabolism.
      ). As such, chronic drug users show a greater preponderance of A1 compared with the general population (
      • Noble E.P.
      Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: A review.
      ,
      • Comings D.E.
      • Muhleman D.
      • Ahn C.
      • Gysin R.
      • Flanagan S.D.
      The dopamine-D(2) receptor gene: A genetic risk factor in substance-abuse.
      ) and increased prevalence of the allele has similarly been shown in obese populations (
      • Spitz M.R.
      • Detry M.A.
      • Pillow P.
      • Hu Y.H.
      • Amos C.I.
      • Hong W.K.
      • et al.
      Variant alleles of the D2 dopamine receptor gene and obesity.
      ,
      • Stice E.
      • Spoor S.
      • Bohon C.
      • Small D.M.
      Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele.
      ,
      • Davis C.A.
      • Levitan R.D.
      • Reid C.
      • Carter J.C.
      • Kaplan A.S.
      • Patte K.A.
      • et al.
      Dopamine for "wanting" and opioids for "liking": A comparison of obese adults with and without binge eating.
      ).
      The mu-opioid receptor gene OPRM1 has also been implicated in heightened responding to drugs of abuse (
      • Hoehe M.R.
      • Kopke K.
      • Wendel B.
      • Rohde K.
      • Flachmeier C.
      • Kidd K.K.
      • et al.
      Sequence variability and candidate gene analysis in complex disease: Association of mu opioid receptor gene variation with substance dependence.
      ,
      • Ray L.A.
      • Hutchison K.E.
      A polymorphism of the mu-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans.
      ). The G allele of OPRM1 is involved in reward and is thought to be overexpressed in individuals with binge-eating tendencies (
      • Davis C.A.
      • Levitan R.D.
      • Reid C.
      • Carter J.C.
      • Kaplan A.S.
      • Patte K.A.
      • et al.
      Dopamine for "wanting" and opioids for "liking": A comparison of obese adults with and without binge eating.
      ). In one study, obese binge eaters were significantly more likely to have the G allele than not, whereas obese participants without binge behaviors did not have greater expression of the allele (
      • Davis C.A.
      • Levitan R.D.
      • Reid C.
      • Carter J.C.
      • Kaplan A.S.
      • Patte K.A.
      • et al.
      Dopamine for "wanting" and opioids for "liking": A comparison of obese adults with and without binge eating.
      ). Instead, obese participants without binge eating displayed a significantly higher presence of the Taq A1 allele, whereas those with binge tendencies were more likely to be A1 absent (
      • Davis C.A.
      • Levitan R.D.
      • Reid C.
      • Carter J.C.
      • Kaplan A.S.
      • Patte K.A.
      • et al.
      Dopamine for "wanting" and opioids for "liking": A comparison of obese adults with and without binge eating.
      ). Thus, there is evidence of a dissociation between the dopamine and opioid neurotransmitter systems’ involvement in binge-eating behaviors in obese individuals, potentially indicating a difference in reward responsivity. The OPRM1 G allele seems to increase pleasure derived from food palatability, manifesting as binge-eating tendencies. Conversely, individuals with Taq A1 and subsequent diminished dopamine expression display reward-deficient characteristics leading to chronic overeating.

      Reward Deficiency Theory

      It can be argued that there is heightened anticipation to reward in individuals at risk for drug abuse or obesity, perhaps stemming from a constitutional decrease in basal dopamine levels, resulting in a hypothetical reward deficiency state. This may place the individual at increased risk for self-medication, whether conscious or subconscious, with drugs of abuse or highly palatable foods. However, the effects of prolonged dopamine receptor stimulation from long-term sugar/fat or drug consumption can result in downregulation of these receptors, leading to a further reduction in sensitivity to dopamine and potentially blunting the response to reward receipt (
      • Bello N.T.
      • Lucas L.R.
      • Hajnal A.
      Repeated sucrose access influences dopamine D2 receptor density in the striatum.
      ,
      • Colantuoni C.
      • Schwenker J.
      • McCarthy J.
      • Rada P.
      • Ladenheim B.
      • Cadet J.L.
      • et al.
      Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain.
      ). This suggests that obese individuals may exhibit tolerance to the rewarding properties of food, as similarly occurs in chronic drug users. The individual then requires greater exposure to rewarding stimuli, whether drugs or food, to achieve the same level of pleasure previously experienced, which can result in an escalation of consumption (
      • Ifland J.R.
      • Preuss H.G.
      • Marcus M.T.
      • Rourke K.M.
      • Taylor W.C.
      • Burau K.
      • et al.
      Refined food addiction: A classic substance use disorder.
      ). This may then become cyclical, with greater amounts needed to counteract the increase in tolerance and to obtain the pleasure originally derived from eating or drug use (Figure 1). This idea of tolerance to food should be pursued empirically, in addition to the anecdotal evidence already reported, and potentially related to D2 receptor downregulation present in obese individuals.
      Figure thumbnail gr1
      Figure 1Reward deficiency circuit demonstrating the initial vulnerability to food or drug dependence from a baseline decreased dopamine D2 receptor availability, contributing to a reward deficient state. This may cause an individual to self-medicate with rewarding stimuli, which may, in turn, cause an exacerbation of the reward-deficient symptoms via a further downregulation of dopamine receptor sensitivity. The overconsumption of highly palatable foods or drugs of abuse can also lead to tolerance, thereby requiring higher doses of these substances and further impacting the striatal dopamine system. Empirical investigations into this notion of tolerance for high-fat/high-sugar food items should be pursued. Additionally, a longitudinal study confirming the decrease in D2 receptor binding potential following severe weight gain, as seen with long-term stimulant abuse, would be extremely valuable to the field.

      Heightened Anticipatory Cue Sensitivity

      Exposure to cues of highly palatable foods can also cause changes in brain activity of overweight individuals and those at genetic risk for obesity. Using a variety of positron emission tomography and functional magnetic resonance imaging paradigms, obese individuals exhibit a greater increase in fronto-striatal circuitry activation during anticipation of high-caloric foods as compared with lean control subjects (
      • Stice E.
      • Spoor S.
      • Bohon C.
      • Veldhuizen M.G.
      • Small D.M.
      Relation of reward from food intake and anticipated food intake to obesity: A functional magnetic resonance imaging study.
      ,
      • Rothemund Y.
      • Preuschhof C.
      • Bohner G.
      • Bauknecht H.C.
      • Klingebiel R.
      • Flor H.
      • Klapp B.F.
      Differential activation of the dorsal striatum by high-calorie visual food stimuli in obese individuals.
      ,
      • Stoeckel L.E.
      • Weller R.E.
      • Cook 3rd, E.W.
      • Twieg D.B.
      • Knowlton R.C.
      • Cox J.E.
      Widespread reward-system activation in obese women in response to pictures of high-calorie foods.
      ). Areas activated include the OFC, ventral and dorsal striatum, cingulate, and amygdala, as well as areas involved in the gustatory circuit (
      • Rolls E.T.
      Sensory processing in the brain related to the control of food intake.
      ), such as the anterior insula, frontal operculum, and somatosensory regions representing the mouth and tongue. Elevated responsivity to food cues may enhance vulnerability to the rewarding properties of food, and blood oxygen level-dependent (BOLD) activation levels positively correlated with BMI in several studies (
      • Stice E.
      • Spoor S.
      • Bohon C.
      • Veldhuizen M.G.
      • Small D.M.
      Relation of reward from food intake and anticipated food intake to obesity: A functional magnetic resonance imaging study.
      ,
      • Rothemund Y.
      • Preuschhof C.
      • Bohner G.
      • Bauknecht H.C.
      • Klingebiel R.
      • Flor H.
      • Klapp B.F.
      Differential activation of the dorsal striatum by high-calorie visual food stimuli in obese individuals.
      ). Given the decrease in striatal D2 receptor availability in obese individuals, it is possible that these increases in activation in response to food cues may be associated with a decrease in D2 receptor levels, the individuals being more susceptible to anticipated reward (
      • Stice E.
      • Spoor S.
      • Bohon C.
      • Veldhuizen M.G.
      • Small D.M.
      Relation of reward from food intake and anticipated food intake to obesity: A functional magnetic resonance imaging study.
      ,
      • Wang G.J.
      • Volkow N.D.
      • Logan J.
      • Pappas N.R.
      • Wong C.T.
      • Zhu W.
      • et al.
      Brain dopamine and obesity.
      ). Positron emission tomography studies investigating dopamine receptor binding and food cue anticipation would be a valuable contribution to the literature to help elucidate this interaction.
      These patterns of activation are mirrored in studies investigating the neural responses to drug cues in substance-dependent individuals. Specifically, greater BOLD activity is seen in the ventral and dorsal striatum, insula, cingulate gyrus, OFC, and prefrontal regions, with activation levels correlating with self-report ratings of craving (
      • Garavan H.
      • Pankiewicz J.
      • Bloom A.
      • Cho J.K.
      • Sperry L.
      • Ross T.J.
      • et al.
      Cue-induced cocaine craving: Neuroanatomical specificity for drug users and drug stimuli.
      ,
      • Volkow N.D.
      • Wang G.J.
      • Telang F.
      • Fowler J.S.
      • Logan J.
      • Childress A.R.
      • et al.
      Cocaine cues and dopamine in dorsal striatum: Mechanism of craving in cocaine addiction.
      ).
      Additional evidence suggests there may be a dissociation between responses during anticipation and consumption of food in obese individuals. Stice et al. (
      • Stice E.
      • Spoor S.
      • Bohon C.
      • Veldhuizen M.G.
      • Small D.M.
      Relation of reward from food intake and anticipated food intake to obesity: A functional magnetic resonance imaging study.
      ,
      • Stice E.
      • Spoor S.
      • Bohon C.
      • Small D.M.
      Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele.
      ) have shown an overactivation in the OFC, striatum, insula, and opercular regions in overweight adolescents during anticipation of food reward. However, during food receipt, there was an inverse correlation between BMI and dorsal striatal activation, such that higher BMI related to a decrease in BOLD response (
      • Stice E.
      • Spoor S.
      • Bohon C.
      • Veldhuizen M.G.
      • Small D.M.
      Relation of reward from food intake and anticipated food intake to obesity: A functional magnetic resonance imaging study.
      ,
      • Stice E.
      • Spoor S.
      • Bohon C.
      • Small D.M.
      Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele.
      ). Decreased activity was also associated with weight gain at 6-month follow-up (
      • Stice E.
      • Yokum S.
      • Blum K.
      • Bohon C.
      Weight gain is associated with reduced striatal response to palatable food.
      ). This is in contrast to normal-weight adolescents with greater familial risk for obesity who show increased caudate and opercular activation in response to food receipt (
      • Stice E.
      • Yokum S.
      • Burger K.S.
      • Epstein L.H.
      • Small D.M.
      Youth at risk for obesity show greater activation of striatal and somatosensory regions to food.
      ). This suggests that young individuals at risk for obesity may initially be hyperresponsive to food, but that over time, due to a downregulation of striatal dopamine receptors from chronic overstimulation, the individual is left in a reward-deficient state. They may then self-medicate through consumption of increasingly larger portions of high-fat/high-sugar foods.

      Structural Abnormalities in Food and Drug Dependence

      In addition to the acute effects of drugs and high-fat/high-sugar foods on the striatal dopamine system, there are long-term changes that occur in brain structure and function of drug- and food-dependent individuals. As stated previously, decreases in D2 receptor binding are associated with OFC hypometabolism in substance-dependent and obese individuals (
      • Volkow N.D.
      • Fowler J.S.
      • Wang G.J.
      • Hitzemann R.
      • Logan J.
      • Schlyer D.J.
      • et al.
      Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers.
      ,
      • Volkow N.D.
      • Chang L.
      • Wang G.J.
      • Fowler J.S.
      • Ding Y.S.
      • Sedler M.
      • et al.
      Low level of brain dopamine D2 receptors in methamphetamine abusers: Association with metabolism in the orbitofrontal cortex.
      ,
      • Volkow N.D.
      • Wang G.J.
      • Telang F.
      • Fowler J.S.
      • Thanos P.K.
      • Logan J.
      • et al.
      Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors.
      ), with BMI negatively correlating with OFC metabolism (
      • Volkow N.D.
      • Wang G.J.
      • Telang F.
      • Fowler J.S.
      • Goldstein R.Z.
      • Alia-Klein N.
      • et al.
      Inverse association between BMI and prefrontal metabolic activity in healthy adults.
      ). Moreover, several studies have reported decreases in frontal cortical gray matter volume in obese individuals, again correlating with BMI, and similar structural deficits are reflected in chronic drug users (
      • Ersche K.D.
      • Jones P.S.
      • Williams G.B.
      • Turton A.J.
      • Robbins T.W.
      • Bullmore E.T.
      Abnormal brain structure implicated in stimulant drug addiction.
      ,
      • Franklin T.R.
      • Acton P.D.
      • Maldjian J.A.
      • Gray J.D.
      • Croft J.R.
      • Dackis C.A.
      • et al.
      Decreased gray matter concentration in the insular, orbitofrontal, cingulate, and temporal cortices of cocaine patients.
      ,
      • Matochik J.A.
      • London E.D.
      • Eldreth D.A.
      • Cadet J.L.
      • Bolla K.I.
      Frontal cortical tissue composition in abstinent cocaine abusers: A magnetic resonance imaging study.
      ).
      These abnormalities are often associated with cognitive deficits, with drug users showing impairments in executive functions such as cognitive control, flexibility, decision making, and working memory (
      • Verdejo-Garcia A.
      • Bechara A.
      • Recknor E.C.
      • Perez-Garcia M.
      Executive dysfunction in substance dependent individuals during drug use and abstinence: An examination of the behavioral, cognitive and emotional correlates of addiction.
      ,
      • Ersche K.D.
      • Clark L.
      • London M.
      • Robbins T.W.
      • Sahakian B.J.
      Profile of executive and memory function associated with amphetamine and opiate dependence.
      ,
      • Bolla K.I.
      • Eldreth D.A.
      • London E.D.
      • Kiehl K.A.
      • Mouratidis M.
      • Contoreggi C.
      • et al.
      Orbitofrontal cortex dysfunction in abstinent cocaine abusers performing a decision-making task.
      ). Similar decreases in orbitofrontal volume and activation in obese individuals would suggest analogous impairments in cognition in this population. As such, executive function difficulties have been seen in overweight and obese individuals (
      • Volkow N.D.
      • Wang G.J.
      • Telang F.
      • Fowler J.S.
      • Goldstein R.Z.
      • Alia-Klein N.
      • et al.
      Inverse association between BMI and prefrontal metabolic activity in healthy adults.
      ,
      • Gunstad J.
      • Paul R.H.
      • Cohen R.A.
      • Tate D.F.
      • Spitznagel M.B.
      • Gordon E.
      Elevated body mass index is associated with executive dysfunction in otherwise healthy adults.
      ,
      • Elias M.F.
      • Elias P.K.
      • Sullivan L.M.
      • Wolf P.A.
      • D'Agostino R.B.
      Lower cognitive function in the presence of obesity and hypertension: The Framingham heart study.
      ), and a decrease in OFC volume correlated with disinhibited eating in obese adolescents (
      • Maayan L.
      • Hoogendoorn C.
      • Sweat V.
      • Convit A.
      Disinhibited eating in obese adolescents is associated with orbitofrontal volume reductions and executive dysfunction.
      ). However, the scope of disability does not appear to be as severe as in drug-dependent individuals. This suggests there is an important distinction in the neurotoxic effects of drugs of abuse on the brain as compared with high-fat/high-sugar foods.

      Action-to-Habit Devolution

      The OFC/prefrontal cortex is critical for self-control, inhibition, and goal representation, and reduced activity in this region is associated with higher levels of impulsivity and compulsivity. Impulsive traits are strongly linked to drug abuse, and compulsive tendencies can lead to an increased susceptibility for addiction (
      • Belin D.
      • Mar A.C.
      • Dalley J.W.
      • Robbins T.W.
      • Everitt B.J.
      High impulsivity predicts the switch to compulsive cocaine-taking.
      ,
      • Dalley J.W.
      • Everitt B.J.
      • Robbins T.W.
      Impulsivity, compulsivity, and top-down cognitive control.
      ,
      • Ersche K.D.
      • Turton A.J.
      • Pradhan S.
      • Bullmore E.T.
      • Robbins T.W.
      Drug addiction endophenotypes: Impulsive versus sensation-seeking personality traits.
      ,
      • Robbins T.W.
      • Gillan C.M.
      • Smith D.G.
      • de Wit S.
      • Ersche K.D.
      Neurocognitive endophenotypes of impulsivity and compulsivity: Towards dimensional psychiatry.
      ). Indeed, we have put forth the action-to-habit theory of addiction, with an increase in impulsively driven, hedonically motivated actions that, through a process of signaling transfer, devolve from ventral to dorsal striatal control, becoming compulsive, habit-driven responses (
      • Robbins T.W.
      • Gillan C.M.
      • Smith D.G.
      • de Wit S.
      • Ersche K.D.
      Neurocognitive endophenotypes of impulsivity and compulsivity: Towards dimensional psychiatry.
      ,
      • Everitt B.J.
      • Robbins T.W.
      Neural systems of reinforcement for drug addiction: From actions to habits to compulsion.
      ). As drug taking is devalued, drug-seeking behavior becomes compulsive and habituated, triggered by salient cues like environment- or drug-related paraphernalia. Overconsumption of palatable foods could initiate a similar devolution from goal-directed to habitual behavior, the consumption of high-fat/high-sugar foods becoming less pleasurable and instead transferring to a compulsive response triggered by cues such as advertisements, mood, and setting (
      • Neal D.T.
      • Wood W.
      • Wu M.
      • Kurlander D.
      The pull of the past: When do habits persist despite conflict with motives?.
      ).
      The critical question remains as to whether these structural and functional changes are predisposing risk factors for addiction or are a consequence of prolonged substance abuse. A recent study investigating stimulant-dependent individuals and their biological siblings suggests that these structural differences may predate heavy drug use, with decreases in gray and white matter seen in both groups (
      • Ersche K.D.
      • Jones P.S.
      • Williams G.B.
      • Turton A.J.
      • Robbins T.W.
      • Bullmore E.T.
      Abnormal brain structure implicated in stimulant drug addiction.
      ). Furthermore, a decrease in prefrontal white matter connectivity was significantly related to impairments on an assessment of motor control and impulsivity, on which both groups were equally impaired (
      • Ersche K.D.
      • Jones P.S.
      • Williams G.B.
      • Turton A.J.
      • Robbins T.W.
      • Bullmore E.T.
      Abnormal brain structure implicated in stimulant drug addiction.
      ). This indicates that cortical abnormalities and accompanying deficits in cognitive control may predispose an individual for drug dependence. However, additional structural changes present in the stimulant users suggest there is an exacerbation of these abnormalities from chronic use.
      Extrapolating this finding to obese individuals, there may be underlying abnormalities in fronto-striatal circuitry and executive function that serve as risk factors for weight gain. However, while the neurotoxic effects of drugs on the central nervous system have long been established, it is less well known whether a high-fat/high-sugar diet and subsequent health problems, such as hypertension, diabetes, and cardiovascular ailments, have similar effects on the brain. It would appear, though, that the acute effects of highly palatable foods on the dopamine-modulated fronto-striatal pathways, similar to drugs of abuse, may exacerbate underlying structural and functional abnormalities in overweight or at-risk individuals, possibly leading to increases in impulsivity and compulsive tendencies. A similar endophenotype study of overweight and normal-weight sibling pairs would be an ideal way to investigate this phenomenon in pathological eating behaviors.

      Distinctions between Food and Drug Consumption

      Despite the many parallels outlined in this review, there are still numerous distinctions between drug addiction and hyperphagia leading to obesity, the most notable being the necessity of food consumption for energy, growth, and survival. As such, there are a multitude of anatomical regions and hormone and neurotransmitter systems that modulate food intake beyond reward and pleasurable responding. The mechanisms implicated in obesity in different individuals could stem from alterations in any one of these systems, causing dysfunction of hunger and satiety signals. Additionally, there is sufficient evidence that the reward responses elicited by highly palatable foods’ action on opioid and dopamine systems are not as potent as those of addictive drugs, which more directly influence these neurochemical pathways (
      • Dichiara G.
      • Imperato A.
      Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.
      ,
      • Opris I.
      • Hampson R.E.
      • Deadwyler S.A.
      The encoding of cocaine vs. natural rewards in the striatum of nonhuman primates: Categories with different activations.
      ). Furthermore, differences in the magnitude of aberrant cognitive processes associated with addictive disorders and obesity are cited above, as well as important distinctions in the physiological symptoms of withdrawal associated with each type of substance. However, these caveats do not diminish the compulsive nature or lack of control associated with binge eating or the neurochemical changes that can occur following chronic sugar and fat consumption, mimicking drug effects. Therefore, in some individuals who struggle with weight and eating behaviors, it is possible that an addiction model would best fit their symptoms and behaviors, and potential treatment options, such as those involving opioid receptor antagonists, could be targeted to them as such.
      DGS is supported by a studentship from the Cambridge Overseas Trust. TWR consults for Cambridge Cognition, Lilly, Lundbeck, GlaxoSmithKline, Shire Pharmaceuticals, and Merck, and Sharp and Dohme. He has recently held research grants from Lilly, GlaxoSmithKline, and Lundbeck. DGS and TWR are both affiliated with the Behavioural and Clinical Neuroscience Institute, which is jointly funded by an award from the Medical Research Council and Wellcome Trust (G00001354).

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