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The Cellular and Molecular Substrates of Anorexia Nervosa, Part 2

Posted Dec 15 2009 7:31pm
Last month, I wrote on Part One of an article from the magazine Psychiatric Times titled "The Cellular and Molecular Substrates of Anorexia Nervosa, Part One." As I promised, I am writing on Part Two now that it has appeared (the original link I found was bad, and I had to hunt down the article, so I apologize for the delay, but here it is!).

The author, John Medina, summarized the first article as follows:

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.

Medina first begins discussing the role of malfunctions in the dopamine system in people with AN, since many anorexics report varying levels of asceticism, anhedonia (the inability to find anything pleasurable), and the difficulties in finding something consistently rewarding. This is otherwise known as the Theme of My Life. These are considered trait features because they often exist before the onset of illness and persist after recovery. Other clues pointing to the dopamine system are difficulties with visual tasks (which can often signal a malfunction in the dopamine system), lower levels of dopamine metabolites in the cerebrospinal fluid even after recovery, variances in the genes of dopamine receptors in the brain, as well as brain imaging studies.

The other major neurotransmitter being studied with respect to anorexia is serotonin. Medina included a diagram (that I've copied here) that portrays the two hypotheses related to abnormalities in the serotonin system that may contribute to anorexia. The first hypothesis is that people with AN have increased levels of serotonin in the brain, which may contribute to the common traits of harm avoidance and anxiety, as well as the general lack of effectiveness of SSRIs in treating AN. The other hypothesis has to do with an imbalance in serotonin receptors which can be altered by both hormonal changes and stress. The evidence for this has to do with the usual onset of AN during puberty/adolescence, and many times the onset coincides with a particularly stressful time in the sufferer's life.

Writes Medina:

Starvation-induced reductions in levels of extracellular 5-HT, for example, might result in reduced stimulation of postsynaptic 5-HT1a and 5-HT2a receptors, leading to behavioral alteration. The resulting dysphoria, normal in unaffected individuals, might be exaggerated in patients with AN.

There are testable questions surrounding these ideas. Forcing AN patients to eat, for example, might stimulate postsynaptic 5-HT1a and 5-HT2a receptor activity. This stimulation would lead to an elevation in dysphoric mood, transforming eating and weight gain activities into traumatic stress-inducing experiences. This might explain the no-win behaviors so common in AN patients. If the patient were allowed to continue to starve herself, anorexigenic information related to neuropeptide alterations (reduced b-endorphins, elevation in stress-related metabolism such as elevated corticotropic-releasing hormone), might exacerbate AN symptoms by driving food-restricting behaviors. Whether eating or starving, the same dysfunctional circuitry would be stimulated, all leading to the symptoms.

... Persons with AN show unique anxiety-related 5-HIAA metabolic perturbations. The weight loss in these patients results in a reduction in 5-HIAA CSF levels. But they concomitantly show dramatically elevated 5-HIAA receptor binding in specific cortical and limbic structures—something not seen in healthy controls. Food might very well be anxiogenic in these individuals.

Which, really, explains both everything and nothing. As Medina says, there is no one neurological system that is both necessary and sufficient for the development of AN. And I hate to rain on anyone's parade, but I doubt it will be just one thing or just one system or just one factor. Human behavior is way too complicated. Still, we have made enormous strides in understanding the scientific basis of anorexia, and I'm looking forward to future research.
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