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The Cellular and Molecular Substrates of Anorexia Nervosa, Part 2

(PSYCHIATRIC TIMES) - I think I am going to talk about the neurobiology of happiness in my next column. The reason has to do with the nature of our 2-month journey into the biology of eating disorders—a subject that, considering the dearth of explanatory data, is tough to write about. It’s also a bit depressing, considering how difficult it can be to treat. This is the second installment in a 2-part series that focuses on the neurobiology of restricting-type anorexia nervosa (AN).

Last month, I discussed behavioral and cellular aspects of AN.1 A testable hypothesis was outlined: AN was described as a conflict between an un-acquired biological need to have food and an acquired negative reaction to it. Patients with AN recruit cortical executive reactions in response to appetite cues, reactions that insert a top-down “food-negative” bias into the normal drives for fuel. These executive reactions are consistently overstimulated in AN patients, leading to high anticipatory behavior and obsessive concern with future events. Derived mostly from noninvasive imaging studies, this notion of conflicting priorities (complete with a dysfunctional reward/punishment system) has surprising empirical support.

But it is hardly the complete story of AN. Besides behavioral and cellular concerns, there are also molecular interactions to consider. It is to these efforts that we turn, focusing on the “usual regulatory suspects” of dopamine and serotonin neurotransmitter biology.

A reason for genes

Many twin studies have been initiated in the attempt to characterize potential underlying genetic components to AN. There has been some success, and in 2 directions. Large-scale studies have demonstrated that between 50% and 85% of the variance observed in AN (and bulimia) can be attributed to genetic factors. The numbers actually suggest a continuum of diffuse but related behaviors—including weight dissatisfaction, weight preoccupation, and dietary restraint.

The second direction takes into account child temperament issues. It has been known for years that specific personality traits observed in adolescence can predispose an individual to AN. These include perfectionism, harm avoidance, and certain obsessive-compulsive behaviors. Genetic studies show these traits to be heritable as well. These are independent of body weight and can be present in unaffected family members.

One is continually confronted with complexity, confounders, and nuance. Not a welcome comment regarding a disease such as anorexia nervosa, which has the highest mortality rate of any psychiatric disorder.

The aggregation of these 2 lines of work gave researchers ample reasons to seek underlying genetic causes for the disorder. They are still looking. Investigation of the obvious choices—dopaminergic and serotonergic systems—has yielded some fruit. But the picture that emerges is far from complete, and at this point gives only tantalizing hints about potential molecular mechanisms.

Dopaminergic interactions

Behavioral work suggested ample reasons to suspect dopamine-pleasure responses might be dysfunctional in AN patients. Afflicted individuals often seem addicted to exercise. They are ascetic, anhedonic, and find precious little in their lives that is consistently rewarding (aside from the pursuit of weight loss). This “trait” versus “state” issue is strengthened because such behavioral patterns persist, albeit in reduced form, after successful treatment. Dysfunction in dopamine regulation, especially in the striatal circuits mentioned last month, might provide an important component to alterations in these behaviors. They may also play a role in the motor functions and decreased food consumption behaviors typically associated with AN.

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