Are Extreme Eating Disorders Caused By Pathobiology Of The Dopamine Reward Circuit?
Controlling food intake and energy balance are an important homeostatic mechanism of the human body, partly mediated by dopamine (DA) pathways in the cerebrum. DA augments the behavioral drive for stimulus reward, although it is not directly responsible for the hedonistic sensation itself. However, this feedback pathway is subject to pathologic reinforcement through aberrant behaviors, which paradoxically could reinforce both the overconsumption of food in Binge Eating Disorder and excessive dieting in Anorexia Nervosa.
Since Barger and Ewens first synthesized DA in 1910, continued investigation has led to important discoveries about its influence on brain activity. The scientific community of the early 20th century believed that DA was simply a precursor for the stress hormone norepinephrine. However, in 1958 Carlson and Hillarp discovered that DA also functions independently as a neurotransmitter.
DA is an integral neurotransmitter of the sympathetic nervous system, and is one of the most abundant catecholamines, the sympathomimetic "fight-or-flight" hormones, which are in response to stress. DA is biosynthesized at the neuronal synapse and adrenal medulla. In the brain, DA has a role in cognition, motor activity, and, in the regulation of behavioral pathways, including motivation and reward. Most of the DA unused during these functions is inactivated by enzymatic breakdown through the reuptake of DA receptors D1, D2, D3, D4, and D5. At this level of the DA circuit, if DA levels reach either extreme, DA receptors are able to downregulate or upregulate their activity. However, dysfunctional regulation of DA receptors, particularly reduced density of D2 receptors, can cause inappropriate feedback, implicated as a contributor to drug addiction and eating disorders.
Binge eating disorder (BED) appears to be caused by abnormal feedback in the DA-mediated reward circuit. People with BED range in weight from normal to obese, but the density of D2 receptors in BED brains has been shown to be inversely correlated with their BMI (Wang et al. 354). It is thought that overconsumption of food in this disorder increases extracellular DA in the nucleus accumbens, part of the brain involved in the reward circuit, as compensation for low D2 receptor density.
The increasing prevalence of obesity and its associated health problems in industrialized nations is a relatively recent phenomenon that surfaced in the past several decades as the food industry expanded its products to include low-cost, high-fat, high-carbohydrate, many of which are considered snack, or comfort foods. The excessive intake of such cheap food having limited nutritional value, coupled with lack of physical activity, is blamed for an increase in health problems, such as diabetes, in modern western societies today.
The consumption of the cheap calories of comfort food might also stimulate the DA-mediated reward circuit, particularly in situations of chronic stress. In a rat model, there was an inverse relationship between DA receptor density and weight gain in rats exposed to chronic stress (Dallman et al. 275). Obese rats with less DA receptor density might be overeating to compensate for decreased activation of the reward feedback loop (Wang et al. 254). Overeating could potentiate this dysfunctional feedback mechanism by further decreasing receptor density, thus leading to increasing food intake. In obese humans, the lack of reward circuit feedback might also be potentiated by societal stigmatization, including job discrimination, social exclusion, exploitation by the diet and fitness industry, denial of health benefits, and maltreatment by health care professionals (Myers and Rosen 221).
Drugs that increase extracellular DA have been shown to reduce obesity in animal models (Wang et al. 356). However, many of these drugs, such as cocaine, have undesirable side effects which negate their therapeutic benefit. Cocaine is an effective means of releasing DA but has limited potential for diet control because of its strong addictive and psychoactive effects (Wang et al. 356). Animals given unlimited access to intravenous cocaine self-administer the drug to the point of death (Volkow and Wise 556).
At the other end of the spectrum of eating disorders, anorexia nervosa (AN) is characterized by pathologic eating behavior that includes a relentless pursuit of thinness, hyperactive motor behavior, obsessive personality profile, and reduced novelty seeking. Although the literature on the role of DA in AN is limited, it appears that AN females have increased D2 receptor activity (Kaye et al. 505). Increased D2 receptors in the striatum, nucleus accumbens, and olefactory tubercle, brain areas involved in human feeding behavior, could explain the relative disinterest in food in patients with AN, based on our understanding of the DA-mediated reward circuit. Also, some of the non-dietary behavioral aspects of AN could be explained by this mechanism, since variations in striatal D2 receptors have been shown to affect hyperactivity, and DA neurons in the nucleus accumbens/limbic region are involved in reward and novelty seeking (Bergen et al. 1704).
Do extremes of dietary behavior cause or simply uncover otherwise transparent defects in the DA feedback circuit? It has been shown that the fashion industry's pressure to maintain waif-like female weight standards can lead to be permanent alteration of these women's metabolism, along with changes in their drive, thoughts, feeling, and behavior (Treasure et al. 243). These behavioral changes in fashion models are similar to those found in AN. Idealized feminine thinness continues to be emphasized in Western nations, despite the health risks of extreme weight loss and AN. Models and other fashion professionals are under pressure to be thin, and excessive exercise and dieting can dominate their lives. In Italy, girls applying to modeling agencies are required to meet the standard image of a "good-looking" female, being at least 1.7m tall and not wearing a dress size larger than small (Preti et al. 92).
Animal experimentation shows that after a period of food restriction, animals will overeat until they get back to their normal weight. However, other mediators, including pathologic behavior (such as forced starvation) and drugs, could disrupt this homeostatic mechanism. (Treasure et al. 243). Drug abuse, particularly cocaine, could result in permanent alterations of the DA reward circuit, particularly in adolescent females who might be more susceptible because of a greater prevalence of eating disorders in this group. Almost 5% of adolescent girls have an eating disorder, making it the third most common chronic illness in this age group (Golden et al. 496). And drug experimentation is more common in adolescents (Winters 3). An investigation that compared the rate of eating disorders and use of illicit drugs among models and other groups of females reported that 35% of fashion models as compared to 12% of controls abused drugs or alcohol (Santonastaso et al. 168). The widespread use of cocaine for extreme dieting among fashion models is easily explained their need for the energy, appetite suppression, and induced euphoria caused by this drug. However, since cocaine is a DA antagonist, the use of this drug in these models could also reinforce an already suppressed DA reward circuit and cause or potentiate AN.
The involvement of multiple brain circuits and their associated behaviors indicate the need for a multifaceted treatment of psychiatric food addictions. Eating disorders represent a significant percentage of national expenditures. The economic impact of obesity was $99.2 billion dollars in 1995 (Wolf and Colditz 97), while the cost of inpatient AN treatment is $30,180 per year (Crow and Nyman 155). Apart from low cost and easy availability, there might be another reason that comfort foods are so prevalent today. It is possible that the cause of BED or AN is multifactorial, requiring an external alteration of the DA feedback circuit. Although eating disorders might therapeutically benefit from altering DA concentration, DA receptors do not appear to directly control the reward circuit possibly explaining why pharmacologic alterations of DA have not had much success in treating eating disorders. However, as our understanding of human brain pharmacology increases, it might be possible in the future to target the appropriate DA receptor, as well as other specific receptors in the brain, to successfully manage and treat eating disorders.
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