Serotonin interactions

Compelling as some of these data are, dopamine is not the only neurotransmitter under active investigation. Other evidence suggests that compared with healthy individuals, people who are susceptible to AN have alterations in normal serotonin biology.

Click to EnlargeMost of the best work has focused on 2 ideas (Figure). The first posits that people vulnerable to an eating disorder have increased extracellular concentrations of serotonin—something that can actually be measured. The second is the presence of an imbalance in postsynaptic serotonin receptor activity. As you will recall, serotonin receptors consist of a family of related proteins. Two of these—the 5-HT1a and 5-HT2a receptors—have received a great deal of research attention.

There is reason to investigate alterations in ligand/receptor binding with these receptor systems in patients who have AN, especially given the mean age at onset. Gonadal steroid changes associated the menstruation (and stress) have been known to alter the activity of the 5-HT system during adolescence. 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.

Do any of these speculations have empirical support? Two lines of evidence suggest an important involvement with serotonin in certain types of AN. However, the specific answers await further research.

• There is specific evidence that patients with AN present with an imbalance in postsynaptic 5-HT1a and 5-HT2a receptor activities in specific areas of the brain. These alterations might contribute to the feelings of abnormal satiety and excessive harm-avoiding, anxiety-riddled behavior.

• 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.

These findings, real as they are, do not provide many solid hints about molecular explanations for AN. To date, no single biochemical alteration has been shown to be both necessary and sufficient to produce the disease. Combined with the dopamine work, one might be tempted to say diseases.

And, I suppose, that is the frustrating point. Whether one is looking at behavioral components, neural circuitry, or molecular interaction, one is continually confronted with complexity, confounders, and nuance. Not a welcome comment regarding a disease such as AN, which has the highest mortality rate of any psychiatric disorder. It is one of the most expensive to treat, too, with no guarantee of success when therapy reaches its end point. Progress has been made, but we have a long way to go before we know everything. Given its urgency, that’s a very depressing thing to write.

Like I said, I think in my next column I am going to talk about the neurobiology of happiness.