The Addictive Dimensionality of Obesity

In the paper

“In the striatum, D2 receptors mediate signaling through the indirect pathway that modulates frontocortical regions, and its down-regulation enhances drug sensitization in animal models (74), whereas its upregulation interferes with drug consumption (75).”

What the sources say

• Partly supported

  The paper’s Abstract reports that transient inhibition of striatopallidal (indirect-pathway) neurons in rats enhanced amphetamine sensitization. It does not show that D2-receptor down-regulation caused this effect or establish signaling to frontocortical regions. The separate drug-consumption claim is attached to citation (75), not this source. (LLM, conf=0.87)

  cites [74] Ferguson, 2011, Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization, Nat Neurosci sourceExperimental — accuracy not yet measured
• Supported

  Citation (75) is attached to the claim that D2 receptor upregulation interferes with drug consumption, not to the preceding claims about indirect-pathway signaling or down-regulation. The Discussion reports that upregulating D2 receptors in the nucleus accumbens reduced cocaine self-administration in rats for up to six days. (LLM, conf=0.94)

  cites [75] Thanos, 2008, D2R DNA transfer into the nucleus accumbens attenuates cocaine self-administration in rats, Synapse source

In the paper

“Dysregulation of striatal D2R signaling has also been implicated in obesity (76,77) and in compulsive food intake in obese rodents (78).”

What the sources say

• Supported

  The citation to this paper supports the obesity portion of the sentence; the separate citation (78) is attached to compulsive food intake in obese rodents. The Conclusion reports lower striatal D2/3 receptor availability in severely obese subjects and a role for the striatal dopaminergic reward system in obesity. (LLM, conf=0.93)

  cites [76] de Weijer, 2011, Lower striatal dopamine D2/3 receptor availability in obese compared with non-obese subjects, EJNMMI Res source
• Partly supported

  The Results and Conclusion report depressed dopamine neurotransmission in the nucleus accumbens and dorsal striatum of dietary-obese rats, supporting a link between striatal dopamine dysfunction and obesity. They address dopamine release, not D2R signaling. The separate citation (78) accompanies the compulsive-food-intake portion of the sentence, so that portion is not attributed to this paper. (LLM, conf=0.88)

  cites [77] Geiger, 2009, Deficits of mesolimbic dopamine neurotransmission in rat dietary obesity, Neuroscience sourceExperimental — accuracy not yet measured
• Supported

  Citation (78) is attached to the claim about compulsive food intake in obese rodents, not the separate obesity claim. The Discussion reports compulsive-like eating in rats with striatal D2R knockdown after extended access to palatable food and links the behavior to deficits in striatal D2R signaling. (LLM, conf=0.94)

  cites [78] Johnson, 2010, Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats, Nat Neurosci source

In the paper

“Indeed, we showed that subjects who, despite having a high genetic risk for alcoholism (positive family history of alcoholism) were not alcoholics, had higher than normal striatal D2R, which was associated with normal prefrontal metabolism (81) that might have protected them from alcoholism.”

What the sources say

• Not checked yetcites [81] Volkow, 2006, High levels of dopamine D2 receptors in unaffected members of alcoholic families: Possible protective factors, Arch Gen Psychiatry source

In the paper

“However, obesity can also result from easy access to highly palatable food, excessive consumption of which can affect homeostatic signaling and disrupt the sensitivity to food reward.”

In the paper

“We present evidence of shared neurobiological substrates and do not claim that obesity is the result of food addiction but rather that food reward plays a critical role in overeating and obesity, referring to it as the dimensional component of obesity.”

In the paper

“Moreover, neurons in VTA and/or nucleus accumbens (NAc) express glucagon-like peptide-1 (11,12), ghrelin (13,14), leptin (15,16), insulin (17), orexin (18), and melanocortin receptors (19).”

What the sources say

• Not checked yetcites [11] Alhadeff, 2012, GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake, Endocrinology source
• Not checked yetcites [12] Rinaman, 2010, Ascending projections from the caudal visceral nucleus of the solitary tract to brain regions involved in food intake and energy expenditure, Brain Res source
• Not checked yetcites [13] Abizaid, 2006, Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite, J Clin Invest source
• Not checked yetcites [14] Jerlhag, 2007, Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens, Addict Biol source
• Not checked yetcites [15] Figlewicz, 2003, Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat, Brain Res source
• Not checked yetcites [16] Leshan, 2010, Ventral tegmental area leptin receptor neurons specifically project to and regulate cocaine- and amphetamine-regulated transcript neurons of the extended central amygdala, J Neurosci source

In the paper

“There is no homeostatic regulator to check the intake of drugs (including alcohol); thus, regulation of drug consumption is mostly driven by self-control or unwanted effects (i.e., sedation for alcohol).”

In the paper

“This could explain the association of obesity with genes involved with DA neurotransmission, such as the DRD2 Taq I A1 allele, which has been associated with addiction (4).”

What the sources say

• Not checked yetcites [4] Blum, 1996, Increased prevalence of the Taq I A1 allele of the dopamine receptor gene (DRD2) in obesity with comorbid substance use disorder: A preliminary report, Pharmacogenetics source

In the paper

“Repeated consumption of a drug, on the other hand, can directly disrupt the reward circuit, its main pharmacologic target.”

In the paper

“Similarly, there are genes at the intersection between reward and homeostatic pathways, like the cannabinoid receptor 1 (CNR1) gene, variations in which have been associated with BMI and obesity risk by most studies (5), as well as with addiction (6).”

What the sources say

• Not checked yetcites [5] Schleinitz, 2010, Role of genetic variation in the cannabinoid type 1 receptor gene (CNR1) in the pathophysiology of human obesity, Pharmacogenomics source
• Not checked yetcites [6] Benyamina, 2010, CNR1 gene polymorphisms in addictive disorders: A systematic review and a meta-analysis, Addict Biol source

In the paper

“Though food intake and body weight are under homeostatic regulation, when highly palatable food is available, the ability to resist the urge to eat hinges on self-control.”

In the paper

“Overall, homeostatic orexigenic signals increase the activity of ventral tegmental area (VTA) DA cells when exposed to food stimuli, whereas anorexigenic ones inhibit DA firing and decrease DA release (10).”

What the sources say

• Not checked yetcites [10] Opland, 2011, Modulation of the mesolimbic dopamine system by leptin, Brain Res source

In the paper

“And, let us also remember in this context that endogenous opioids are involved in hedonic responses to food and to drugs and that the functional A118G polymorphism in the μ-opioid receptor gene (OPRM1) has been associated with vulnerability for binge-eating disorders (7) and alcoholism (8).”

What the sources say

• Not checked yetcites [7] Davis, 2009, Dopamine for “wanting“ and opioids for “liking“: A comparison of obese adults with and without binge eating, Obesity (Silver Spring) source
• Not checked yetcites [8] Ray, 2011, The role of the Asn40Asp polymorphism of the mu opioid receptor gene (OPRM1) on alcoholism etiology and treatment: A critical review, Alcohol Clin Exp Res source

In the paper

“There is increasing evidence that disruption of energy homeostasis can affect the reward circuitry and that overconsumption of rewarding food can lead to changes in the reward circuitry that result in compulsive food intake akin to the phenotype seen with addiction.”

In the paper

“We propose that these two diseases share neurobiological processes that, when disrupted, can result in compulsive consumption, while also involving unique neurobiological processes.”

In the paper

“This is particularly true whenever high-calorie content food is widely available, not just as a source of nutrition, but also as a strong reward that, by itself, promotes eating.”

In the paper

“The magnitude of these DA increases in addicted subjects predicts the intensity of cue-induced cravings (48), and in animals, they predict the effort that an animal is willing to exert to get the drug (49).”

What the sources say

• Not checked yetcites [48] Volkow, 2006, Cocaine cues and dopamine in dorsal striatum: Mechanism of craving in cocaine addiction, J Neurosci source
• Not checked yetcites [49] Vanderschuren, 2005, Involvement of the dorsal striatum in cue-controlled cocaine seeking, J Neurosci source

In the paper

“Similarly, human studies found an inverse relationship between BMI and illicit drug use (21) and a lower risk for substance use disorders in obese individuals (22), including lower rates of nicotine (23) and marijuana (24) abuse.”

What the sources say

• Not checked yetcites [21] Bluml, 2012, Relationship between substance use and body mass index in young males, Am J Addict source
• Not checked yetcites [22] Simon, 2006, Association between obesity and psychiatric disorders in the US adult population, Arch Gen Psychiatry source
• Not checked yetcites [23] Blendy, 2005, Reduced nicotine reward in obesity: Cross-comparison in human and mouse, Psychopharmacology (Berl) source

In the paper

“Since drugs activate brain reward pathways more potently than food, this helps explain (together with homeostatic satiety mechanisms) the greater ability of drugs to induce loss of control and compulsive consummatory behavior.”

In the paper

“For example, upon first exposure to a food reward, the firing of DA neurons in the VTA increases with a resulting increase in DA release in the NAc (32).”

What the sources say

• Not checked yetcites [32] Norgren, 2006, Gustatory reward and the nucleus accumbens, Physiol Behav source

In the paper

“This possibility is consistent with a recent report in which a D1-like antagonist blocked and a D2-like antagonist increased the reinstatement of food-seeking behavior (37).”

What the sources say

• Not checked yetcites [37] Ball, 2011, Opposing roles for dopamine D1- and D2-like receptors in discrete cue-induced reinstatement of food seeking, Behav Brain Res source

In the paper

“Surprisingly, both addicted and obese subjects exhibit less activation of reward circuits when given the drug or the palatable food, respectively (45).”

What the sources say

• Not checked yetcites [45] Stice, 2008, Relation of reward from food intake and anticipated food intake to obesity: A functional magnetic resonance imaging study, J Abnorm Psychol source

In the paper

“Moreover, since the increases in DA induced by the conditioned stimulus predict the behavioral price the animal is willing to pay to receive it, this will ensure that the motivational drive (fueled by DA signaling) occurs before the animal is eating the food itself.”

In the paper

“Indeed, DA-deficient mice die of starvation, likely as a result of a decreased motivation to consume the food, and replenishing the dorsal striatum with DA restores feeding and rescues them (28).”

What the sources say

• Not checked yetcites [28] Palmiter, 2008, Dopamine signaling in the dorsal striatum is essential for motivated behaviors: Lessons from dopamine-deficient mice, Ann N Y Acad Sci source

In the paper

“Consistent with preclinical studies, imaging studies have also shown that anorexigenic peptides (e.g., insulin, leptin, peptide YY) decrease the sensitivity of the brain reward system to food reward, whereas orexigenic ones (e.g., ghrelin,) increase it [see review (44)].”

What the sources say

• Not checked yetcites [44] Volkow, 2011, Reward, dopamine and the control of food intake: Implications for obesity, Trends Cogn Sci source

In the paper

“Drugs of abuse work by activating the DA reward circuit, which, if chronic, in vulnerable individuals, can result in addiction.”

In the paper

“Indeed, high-calorie foods can promote overeating (i.e., eating that is uncoupled from energetic needs) and trigger learned associations between the stimulus and the reward (conditioning).”

In the paper

“Moreover, interventions that decrease BMI and reduce plasma levels of insulin and leptin enhance the sensitivity to psychostimulant drugs (25),”

What the sources say

• Not checked yetcites [25] Davis, 2010, Insulin, leptin and reward, Trends Endocrinol Metab source

In the paper

“Since this is not what is seen in the clinic, it was suggested that blunted DA activation by consumption (of drug or food) could trigger overconsumption to compensate for the blunted response of the reward circuit (46).”

What the sources say

• Not checked yetcites [46] Stice, 2008, Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele, Science source

In the paper

“In humans, the ingestion of palatable food releases DA in the striatum in proportion to the ratings of meal pleasantness (42) and activates reward circuitry (43).”

What the sources say

• Not checked yetcites [42] Small, 2003, Feeding-induced dopamine release in dorsal striatum correlates with meal pleasantness ratings in healthy human volunteers, Neuroimage source
• Not checked yetcites [43] Volkow, 2008, Overlapping neuronal circuits in addiction and obesity: Evidence of systems pathology, Philos Trans R Soc Lond B Biol Sci source

In the paper

“Certain foods, particularly those rich in sugars and fat, are also potently rewarding (40) and can trigger addictive like behaviors in laboratory animals (41) and humans (27).”

What the sources say

• Not checked yetcites [40] Lenoir, 2007, Intense sweetness surpasses cocaine reward, PLoS One source
• Not checked yetcites [41] Avena, 2008, Evidence for sugar addiction: Behavioral and neurochemical effects of intermittent, excessive sugar intake, Neurosci Biobehav Rev source
• Not checked yetcites [27] Volkow, 2007, Issues for DSM-V: Should obesity be included as a brain disorder?, Am J Psychiatry source

In the paper

“Brain DA pathways, which modulate the behavioral responses to environmental stimuli, play central roles in obesity (also in addiction).”

In the paper

“Still, stress is associated with increased consumption of palatable foods and weight gain and a potentiated OFC activation to food rewards (57).”

What the sources say

• Not checked yetcites [57] Rudenga, 2012, Acute stress potentiates brain response to milkshake as a function of body weight and chronic stress [published online ahead of print March 20], Int J Obes (Lond)

In the paper

“Also, when cocaine-addicted subjects purposefully inhibited craving when exposed to drug cues, those who were successful decreased metabolism in medial OFC (processes motivational value of a reinforcer) and NAc (predicts reward) (55), consistent with the involvement of OFC, ACC, and striatum in the enhanced motivation to procure the drug seen in addiction.”

What the sources say

• Not checked yetcites [55] Volkow, 2009, Cognitive control of drug craving inhibits brain reward regions in cocaine abusers, Neuroimage source

In the paper

“Indeed, DA also modulates motivation and persistence (58).”

What the sources say

• Not checked yetcites [58] Salamone, 2007, Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits, Psychopharmacology (Berl) source

In the paper

“Indeed, several lines of research support a functional link between OFC impairment and disordered eating, including the reported association between disinhibited eating in obese adolescents and reduced OFC volume (66).”

What the sources say

• Not checked yetcites [66] Maayan, 2011, Disinhibited eating in obese adolescents is associated with orbitofrontal volume reductions and executive dysfunction, Obesity (Silver Spring) source

In the paper

“It appears as if DA activation of the striatum by cues (including drug-related contexts) is involved with the desire (wanting), as the trigger of behaviors geared toward consuming the desired reward.”

In the paper

“There is evidence that the OFC also supports conditioned cue-elicited feeding (64) and that it contributes to overeating, irrespective of hunger signals (65).”

What the sources say

• Not checked yetcites [64] Holland, 2005, A neural systems analysis of the potentiation of feeding by conditioned stimuli, Physiol Behav source
• Not checked yetcites [65] Ogden, 1990, Cognitive restraint and sensitivity to cues for hunger and satiety, Physiol Behav source

In the paper

“Similarly, a pre-existing dysfunction of prefrontal regions could also underlie the vulnerability for excessive drug or food consumption, which would be further exacerbated by decreases in striatal D2R (either drug- or stress-induced; it is unclear whether obesogenic diets decrease striatal D2R).”

In the paper

“Moreover, inhibition of striatal D2R or activation of D1 receptor-expressing striatal neurons (mediate signaling in the striatal direct pathway) enhances the sensitivity to drug rewards (74).”

What the sources say

• Not checked yetcites [74] Ferguson, 2011, Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization, Nat Neurosci source

In the paper

“Indeed, imaging studies showed that when nonobese male subjects were asked to inhibit their craving for food when exposed to food cues, they decreased activity in amygdala, OFC, hippocampus, insula, and striatum; and OFC decreases were associated with reductions in food craving (54).”

What the sources say

• Not checked yetcites [54] Wang, 2009, Evidence of gender differences in the ability to inhibit brain activation elicited by food stimulation, Proc Natl Acad Sci U S A source

In the paper

“In addition, because impairments in OFC and ACC are associated with compulsive behaviors and impulsivity, impaired modulation of dopamine in these regions is likely to contribute to the compulsive and impulsive patterns of drug (addiction) or food (obesity) intake.”

In the paper

“In contrast to the decreases in prefrontal activity reported in detoxified cocaine abusers when not stimulated with drug or drug cues [see review (59)], ventral and medial prefrontal regions (including OFC and ventral ACC) become activated with exposure to craving-inducing stimuli (either drugs or cues) (60,61).”

What the sources say

• Not checked yetcites [59] Volkow, 2009, Imaging dopamine's role in drug abuse and addiction, Neuropharmacology source
• Not checked yetcites [60] Grant, 1996, Activation of memory circuits during cue-elicited cocaine craving, Proc Natl Acad Sci U S A source
• Not checked yetcites [61] Wang, 1999, Regional brain metabolic activation during craving elicited by recall of previous drug experiences, Life Sci source

In the paper

“Because drug taking becomes the main motivational drive in addiction, addicted subjects are aroused and motivated by the process of obtaining the drug but withdrawn and apathetic when exposed to non–drug-related activities.”

In the paper

“In contrast, greater volumes of the medial OFC were seen in both bulimia nervosa and binge-eating disorder patients (67), and damage to the OFC in rhesus monkeys has been reported to result in hyperphagia (68).”

What the sources say

• Not checked yetcites [67] Schafer, 2010, Regional grey matter volume abnormalities in bulimia nervosa and binge-eating disorder, Neuroimage source
• Not checked yetcites [68] Machado, 2007, Measuring reward assessment in a semi-naturalistic context: The effects of selective amygdala, orbital frontal or hippocampal lesions, Neuroscience source

In the paper

“The OFC is similarly involved in attributing salience value to food (62), helping to assess its expected pleasantness and palatability as a function of its context.”

What the sources say

• Not checked yetcites [62] Grabenhorst, 2008, How cognition modulates affective responses to taste and flavor: Top-down influences on the orbitofrontal and pregenual cingulate cortices, Cereb Cortex source

In the paper

“Imaging studies revealed that reduced availability of striatal D2R receptors is a consistent abnormality across a wide variety of drug addictions and one that can persist months after detoxification [reviewed in (59)].”

What the sources say

• Not checked yetcites [59] Volkow, 2009, Imaging dopamine's role in drug abuse and addiction, Neuropharmacology source

In the paper

“The insula is also a primary gustatory area, which participates in many aspects of eating behaviors, such as taste.”

In the paper

“In contrast, subjects who have recovered from anorexia nervosa show less insular activation when tasting sucrose and no association of feelings of pleasantness with insular activation as observed in control subjects (104).”

What the sources say

• Not checked yetcites [104] Wagner, 2008, Altered insula response to taste stimuli in individuals recovered from restricting-type anorexia nervosa, Neuropsychopharmacology source

In the paper

“The insula, particularly its more anterior regions, is reciprocally connected to several limbic regions and supports interoceptive functions, integrating the autonomic and visceral information with emotion and motivation and providing conscious awareness of these urges (95).”

What the sources say

• Not checked yetcites [95] Naqvi, 2009, The hidden island of addiction: The insula, Trends Neurosci source

In the paper

“More recently, Parylak et al. (106) have proposed that a similar transition may occur in food addiction with exposure to obesogenic foods.”

What the sources say

• Not checked yetcites [106] Parylak, 2011, The dark side of food addiction, Physiol Behav source

In the paper

“Other studies found significant decreases in blood flow in the prefrontal cortex associated with higher weight in healthy control subjects (84,85), and a functional magnetic resonance imaging study reported impaired executive function in obese women (86).”

What the sources say

• Not checked yetcites [84] Willeumier, 2012, Elevated body mass in National Football League players linked to cognitive impairment and decreased prefrontal cortex and temporal pole activity, Transl Psychiatry source
• Not checked yetcites [85] Willeumier, 2011, Elevated BMI is associated with decreased blood flow in the prefrontal cortex using SPECT imaging in healthy adults, Obesity (Silver Spring) source
• Not checked yetcites [86] Kishinevsky, 2012, fMRI reactivity on a delay discounting task predicts weight gain in obese women, Appetite source

In the paper

“For example, a magnetic resonance imaging study of elderly women found a negative correlation between BMI and gray matter volumes (including frontal regions), which, in the OFC, correlated with impaired executive function (83).”

What the sources say

• Not checked yetcites [83] Walther, 2010, Structural brain differences and cognitive functioning related to body mass index in older females, Hum Brain Mapp source

In the paper

“For example, when normal weight women tasted a sweetener with calories (sucrose), both the insula and DA midbrain areas became activated, whereas tasting a calorie-free sweetener (sucralose) only activated the insula (103).”

What the sources say

• Not checked yetcites [103] Frank, 2008, Sucrose activates human taste pathways differently from artificial sweetener, Neuroimage source

In the paper

“The dark side of addiction was initially proposed by Koob and Le Moal (105) to describe the transition that drug-addicted individuals experience between the initial, pleasurable use of drugs to the one that, with repeated use, results in drug consumption to relieve negative emotional states.”

What the sources say

• Not checked yetcites [105] Koob, 2005, Plasticity of reward neurocircuitry and the 'dark side' of drug addiction, Nat Neurosci source

In the paper

“The habenula is also implicated in food reward: neurons in the rostromedial tegmental nucleus, which receive a major input from the lateral habenula, project to VTA DA neurons and are activated after food deprivation (110).”

What the sources say

• Not checked yetcites [110] Jhou, 2009, The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses, Neuron source

In the paper

“Central to their model is an enhanced sensitivity of the extended amygdala and increased signaling through corticotropin-releasing factor and corticotropin-releasing factor related peptides, which mediate responses to stress.”

What the sources say

• Not checked yetcites [106] Parylak, 2011, The dark side of food addiction, Physiol Behav source

In the paper

“This model helps explain the proliferating examples of contact points between obesity and addiction, some of which were highlighted in this review.”

In the paper

“It is telling that the two largest preventable threats to public health (smoking and obesity) involve the reward circuit that drives the motivation of individuals to consume rewards despite the fact that they are harmful to their health.”

In the paper

“Thus, an enhanced sensitivity of the habenula, as a result of chronic drug exposure, could underlie a greater reactivity to drug cues and also contribute to dysphoric states during withdrawal.”