Anorexia nervosa (AN), a disorder of women,is characterized by restricted eating weight loss an increased physical activity. AN patients invariably have body image distortions, obsessions perfectionism, and behavioral inhibition, as well as depression and anxiety. New data shows these later behaviors persist in AN women after recovery. Moreover, both ill and recovered AN symptoms. Studies in animals and other human populations suggest that increased 5HT neurotransmission may contribute to overly inhibited behavior and satiety and perhaps obsessions and anxiety. This competitive renewal will determine (1) whether increased 5HT neurotransmission occurs at all states of AN: and (2) whether increased 5HT neurotransmission plays a role in the expression of typical AN symptoms such as restricted eating behavioral constraint, perfectionism and increased physical activity.
In AIM ONE we will study AN women at 3 states of illness (underweight, short-term recovered long-term recovered) and 26 healthy control women over 4 years. We will test the hypothesis that AN women have increased 5HT neurotransmission (perhaps by upregulation of postsynaptic 5HT receptors) using a random, double-blind placebo-controlled design in which we administer 3 challenges on 3 different days; 1) d-fenifluramine (d-FF), which increases 5HT release from nerve terminals and inhibits 5HT reuptake, to determine whether increased 5HT neurotransmission exacerbates core AN symptoms; 2) an amino acid mixture that is deficient in the 5HT precursor tryptophan (TRP) to test the hypothesis that reduced 5HT neurotransmission will ameliorate core AN symptoms; 3) a """"""""placebo"""""""" control.
In AIM TWO we will assess 5HT and related neurotransmitters in a rat model in which food restriction and running wheel access produces an animal which self-imposes semistarvation and greatly increases physical activity, a pattern observed in many patients with AN. In this model we can measure 1) relationship of 5HT synthesis and turnover in relationship to pre-and postsynaptic 5HT indices between acute and chronic stages.
AIM THREE is a pilot study to determine whether there are abnormalities in candidate genes related to 5HT neurotransmission in patients with AN. This application seeks to understand the physiologic mechanisms that contribute to pathogenesis of this treatment-resistant illness so that better treatments may be devised.
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