Anorexia nervosa, perfectionism, and dopamine D4 receptor (DRD4)

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2008

Objective: The sensitivity of dopamine reward pathways has been implicated in the risk for various psychiatric disorders including compulsive overeating. The evidence is divided, however, about the direction of causal association. One argument is that a Reward Deficiency Syndrome is the risk factor, while others contend that hyper-sensitivity to reward enhances the motivation for pleasurable activities like eating. Unfortunately, little human research has bridged the gap between psychological and neurobiological approaches to brain reward functioning and disorder. The present study addressed this issue by implementing psychological and biological markers of reward sensitivity in the assessment protocol. Methods: Adults with binge eating disorder (BED) were compared to samples of normal-weight and obese controls on two personality measures of reward sensitivity and were genotyped for six markers of the DRD2 dopamine receptor gene. Results: Genotype × Group ANOVAs revealed significant main effects and an interaction on the personality measures for Taq1A. BED and obese subjects reported greater reward sensitivity than normal-weight controls, but only among those carrying the A1 allele. We also found that normalweight controls with at least one copy of the T allele of the C957T marker had significantly lower reward sensitivity scores than any of the other groups who did not differ from each other. Conclusions: Given evidence linking the A1 allele with reduced receptor density, an inverse relationship was expected between psychological measures of reward sensitivity and presence of the A1 allele. One explanation for our findings could be that the BED and obese participants possess another genetic variant that interacts with the A1 allele to produce higher dopamine activity. These findings have implications for future studies of the molecular genetics of BED and obesity, and for behavioural and pharmacologic therapies targeting these conditions.

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2012

Objective: While the study of binge eating disorder (BED) has burgeoned in the past decade, an understanding of its neurobiological underpinnings is still in the early stages. Previous research suggests that BED may be an overeating syndrome characterized by a hyper-responsiveness to reward, and a strong dopamine signaling in the neuro-circuitry that regulates pleasure and appetitive behaviors. We investigated the D2 receptors genes (DRD2/ANKK1) and their relation to the BED phenotype and four sub-phenotypes of BED that reflect an enhanced response to positive food stimuli. Methods: In a sample of 230 obese adults with and without BED, we genotyped five functional markers of the D2 receptor: rs1800497, rs1799732, rs2283265, rs12364283, and rs6277, and assessed binge eating, emotional eating, hedonic eating, and food craving from dimensionally-scored, self-report questionnaires. Results: Compared to weight-matched controls, BED was significantly related to the rs1800497 and rs6277 genotypes that reflect enhanced dopamine neurotransmission. BED participants were also less likely to carry the minor T allele of rs2283265. The same markers related to the sub-phenotypes of BED with rs1800497 showing the strongest effects in the predicted direction.

Nutrients

The dopamine D4 receptor (DRD4) has a predominant expression in the prefrontal cortex (PFC), brain area strictly involved in the modulation of reward processes related to both food and drug consumption. Additionally, the human DRD4 gene is characterized by a variable number of tandem repeats (VNTR) in the exon 3 and, among the polymorphic variants, the 7-repeat (7R) allele appears as a contributing factor in the neurobiological mechanisms underlying drug abuse, aberrant eating behaviors and related comorbidities. The 7R variant encodes for a receptor with a blunted intracellular response to dopamine, and carriers of this polymorphism might be more tempted to enhance dopamine levels in the brain, through the overconsumption of drugs of abuse or palatable food, considering their reinforcing properties. Moreover, the presence of this polymorphism seems to increase the susceptibility of individuals to engage maladaptive eating patterns in response to negative environmental stimuli. This...

Neuropsychopharmacology, 2007

Response to psychomotor stimulants is highly variable across individuals. Such inconsistencies are influenced by many factors including drug dose and polymorphic differences in genes that encode proteins, such as the dopamine transporter (DAT1), which are relevant to the site of action of these substances. The current study used a double blind, crossover (methylphenidate vs placebo) design to assess DAT1 genotype differences on appetite ratings to a snack-food cue in subjects with binge eating disorder (BED) (n ¼ 32) and healthy agematched controls (n ¼ 46). ANOVA results indicated a significant genotype  diagnostic group interaction whereby BED subjects with at least one copy of the 9-repeat allele showed a significant suppression of appetite in response to methylphenidate compared with controls with this allele, or to subjects with the 10/10 genotype (irrespective of diagnosis) whose drug response was indistinguishable from placebo. The most probable explanation for these findings is that some, currently unknown, genetic variant, which is overrepresented in those with BED, interacts with DAT1 to suppress appetite in response to stimulant administration. The current findings have implications for treatment response to drugs currently in use (or being developed) for the treatment of overeating and overweight.

Nutrition, 2009

Nutrition, 2000

Because daily food intake is the product of the size of a meal and the frequency of meals ingested, the characteristic of meal size to meal number during a 24-h light-dark cycle constitutes an identifiable pattern specific to normal states and obesity and that occurs during early cancer anorexia. An understanding of simultaneous changes in meal size and meal number (constituting a change in feeding patterns) as opposed to an understanding of only food intake provides a more insightful dynamic picture reflecting integrated behavior. We have correlated this to simultaneous changes in dopamine and serotonin concentrations and to their postsynaptic receptors, focusing simultaneously on two discrete hypothalamic food-intake-related nuclei, in response to the ingestion of food. The relation between concentrations of dopamine and serotonin limited to the lateral hypothalamic area (LHA) and the ventromedial nucleus (VMN) as they relate to the influence of meal size and meal number during the hyperphagia of obesity and anorexia of cancer as measured in our experiments are discussed. Based on these data, conceptual models are proposed concerning: 1) an "afferent-efferent neurotransmitter unit," with facilitatory or inhibitory neuropeptide properties to generate an appropriate neuroendocrine and neuronal response that ultimately modifies food intake; 2) initiation and termination of a meal, thereby determining the number and size of a meal under normal conditions; and 3) a schema integrating the onset mechanism of cancer anorexia. Nicotine is used as a tool to further explore the relation of meal size to meal number, with a focus on simultaneous changes in dopamine and serotonin concentrations in the LHA and VMN with the onset of acute anorexia of nicotine infusion and acute hyperphagia of nicotine cessation. Data concerning the role of sex-related hormones on dopamine and serotonin with regard to the LHA and VMN in relation to the modulation of food intake are also presented. Nutrition 2000;16:843-857.

Neuroscience and biobehavioral reviews, 2015

We have suggested that reduced food intake increases the risk for anorexia nervosa by engaging mesolimbic dopamine neurons, thereby initially rewarding dieting. Recent fMRI studies have confirmed that dopamine neurons are activated in anorexia nervosa, but it is not clear whether this response is due to the disorder or to its resulting nutritional deficit. When the body senses the shortage of nutrients, it rapidly shifts behavior toward foraging for food as a normal physiological response and the mesolimbic dopamine neurons may be involved in that process. On the other hand, the altered dopamine status of anorexics has been suggested to result from a brain abnormality that underlies their complex emotional disorder. We suggest that the outcomes of the treatments that emerge from that perspective remain poor because they target the mental symptoms that are actually the consequences of the food deprivation that accompanies anorexia. On the other hand, a method that normalizes the diso...

Nutrition, 2000

Because daily food intake is the product of the size of a meal and the frequency of meals ingested, the characteristic of meal size to meal number during a 24-h light–dark cycle constitutes an identifiable pattern specific to normal states and obesity and that occurs during early ...

TERRY, PHILIP, DAVID B GILBERT AND STEVEN J COOPER. Dopaminereceptor subtypeagonists and feeding behavior. Obes Res. 199S;3(Suppl4):SlSS-S23S. Stimulation or blockade of various dopamine receptor subtypes is associatedwith reducedfeeding. Forexample,D, receptor agonists suppress feeding in food-deprived and free-feeding rats, and in rats given access to a highly palatable diet. Similarly,reducedfoodintake is associated with the actions of diverse D, receptor agonists, and these compounds can interact synergistically with D, receptor agonists to potentiate reductions in feeding. Using micro-structural analysis to compare D, and D, agonist effects, specific differences emerge in their modes of action. D, agonists reduce the duration of feeding, primarily by decreasing the frequency of feeding bouts, whereas D, ago-nists reduce the local rate of eating. However, since D, agonists uniquely reduce feeding in the absence of other behavioralimpairments and are less disruptive of the pattern of feeding behavior, it has been suggested that D, agonists aremore likely than D, agonists to act on central mechanisms regulating food intake. Moreover, only D, agonists are effective in suppressing sucrose sham-feeding , suggesting that D, receptor stimulationmay promote satiety. Nevertheless, many questions remain. For example, antagonist studies have implicated 5-HT receptor stimulation in the anorectic effects of D, agonists, suggesting that further pharmacological and behavioral analyses of receptor -subtype agonist effects are required. Above all, recent developments in the classification of dopamine receptor subtypes reveal the need for new studies examining the involvement of D,, D, and D, receptors infeeding.

Obesity, 2011

Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [ 11 C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocks the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating.