The Cellular and Molecular Substrates of Anorexia Nervosa, Part 2

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 (in Part 1), 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.

Four lines of evidence support an involvement of dopaminergic processes in at least some types of AN:

• Concentrations of dopamine metabolites in the cerebrospinal fluid (CSF) of both affected individuals and recovered individuals are lower than in those without AN.

• Patients who have AN often present with difficulties in certain visual discrimination learning tasks. This is not a trivial finding. Studies show that such impairment often reflects a malfunction in dopamine-signaling.

• There are dopamine receptor (DR) D2 gene polymorphisms associated with those suffering from AN. (DRD2 is one of a family of dopamine receptors in the human genome.) A polymorphism is an aberration in its normal gene structure. The more tightly the polymorphism is associated with a given behavior, the more likely it is to exert an influence on it.

• Noninvasive imaging studies-positron emission tomography (PET) scans, mostly-found a surprising restoration in dopamine receptor binding activity in recovered patients. (Previous work had shown deficits.) Successfully treated patients presented with a dramatic increase in DRD3 binding-another dopamine receptor-in the ventral striatum. As you recall, the ventral striatum helps regulate reward stimuli. Its function played a prominent role in the cellular explanation put forward in the previous column. It must be noted that these PET scans are interpreted as changes in activity, but that could mean many things. The signals could indicate increased DRD3 densities, decreased extracellular dopamine, or both, in recovered patients.

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.

Most 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-HT_1a and 5-HT_2a 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-HT_1a and 5-HT_2a 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-HT_1a and 5-HT_2a 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-HT_1a and 5-HT_2a 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.

PRIMARY REFERENCES BEHIND THE DATA IN THIS SERIES
Kaye WH, Fudge JL, Paulus M. New insights into symptoms and neurocircuit function of anorexia nervosa. Nat Rev Neurosci. 2009;10:573-584.

Conna F, Campbell IC, Katzman M, et al. A neurodevelopmental model for anorexia nervosa. Physiol Behav. 2003;79:13-24.

Klump K, Burt SA, McGue M, Iacono WG. Changes in genetic and environmental influences on disordered eating across adolescence: a longitudinal twin study. Arch Gen Psych. 2007;64:1409-1415.

References:

Reference

1. Medina JJ. The cellular and molecular substrates of anorexia nervosa, part 1. Psychiatr Times. 2009;16(11):18-20.