Neural circuits underlying hyperactivity in an animal model for anorexia nervosa

Abstract

Anorexia nervosa (AN) means literally “a nervous loss of appetite” and is characterized by reduced food intake, extreme body weight loss, hypothermia, amenorrhea and emaciation. The average prevalence of AN has been reported to be 0.3% and has the highest mortality rate (>10%) of all psychiatric disorders. Excessive physical activity is demonstrated by many, if not most, patients with AN at some point in the course of the disorder, and has been described as a hallmark feature of the syndrome. The prevalence of hyperactivity varies widely between 31-80%, due to a lack of clear definition of hyperactive behavior in AN patients. Pharmacotherapy thus far played only a limited role in the treatment of AN and the fact that there are no effective drugs to treat AN argues against a straight forward involvement of common neurotransmitters in the etiology of AN. The neural mechanisms underlying AN remain obscure. Disturbances in dopamine and serotonin neurotransmission and to a limited extent in some peripheral hormones have been described in AN. Studies on the frequently used animal model for AN, the activity-based anorexia model, suggest a normal starvation response at the level of the hypothalamus in the brain. Regulation of food intake and body weight involves complex interactions between peripheral signals and neural circuits that influence metabolism and behavior. Dysfunction of this energy balance regulatory system may underlie eating disorders, such as AN. In the present thesis we focused on regulatory neuronal pathways underlying anorectic behavior and the possible involvement of endocrine signaling with special emphasis on the involvement of the mesolimbic dopaminergic system. We thereby concentrated on starvation-induced hyperactivity, since this trait appears prominent in patients suffering from AN. The overall aim of this thesis was to identify the neural mechanism(s) underlying starvation-induced hyperactivity in order to better understand the pathophysiology seen in AN patients. First we determined which brain areas are involved in starvation-induced hyperactivity. Important hypothalamic brain areas known to be involved in the regulation of food intake were also identified to play a significant role in starvation-induced hyperactivity. Second, we determined the role of dopamine and its receptors by two different approaches; by blockade of dopamine receptors in the brain, and by measuring extracellular levels of dopamine release in the nucleus accumbens, a brain area known to be involved in food regulation and dopamine signaling. Next, we investigated the contribution of peripheral signals, leptin and ghrelin, in starvation-induced hyperactivity. We thereby identified that lack of leptin signaling in the ventral tegmental area of the brain accelerates starvation-induced hyperactivity. Moreover, blockade of ghrelin signaling reduces starvation-induced hyperactivity. Finally, we identified genetic loci and possible candidate genes underlying starvation-induced hyperactivity. Further research is needed to confirm whether the candidate genes are truly involved in AN. As a final point, this thesis provides novel data on the role of ghrelin, leptin and dopamine in particular on the hyperactivity observed in the ABA model. These data give new insights into the mechanisms underlying starvation-induced hyperactivity that may also underlie hyperactivity as observed in AN.