Several lines of indirect evidence suggest that brain serotonin alterations occur in women with anorexia nervosa (AN) and bulimia nervosa (BN) when they are ill and after recovery. In theory, a trait-related increase of 5-HT neurotransmission may contribute to vulnerabilities (restricted feeding, obsessions with order and perfectionism, harm avoidance and negative affect) that contribute to developing AN and BN. In turn, malnutrition may reduce 5-HT neuronal activity, which in turn reduces dysphoric affective states, particularly in AN. New technologies offer the potential of direct characterization of dynamic relations between 5-HT receptor function and human behavior. In the short term (years 1 to 4), funded studies will investigate five groups of women 18 to 45 years old: 1) ill AN and BN women; 2) recovered AN and BN women (greater than 1 year normal menses, no binging and purging, and healthy and stable weight); and 3) healthy control women.
In Aim 1, 150 PET imaging and 18-F-altanserin will assess 5-HT-2A postsynaptic receptor binding. Preliminary data support the possibility that recovered AN and BN women will have a reduction of orbitofrontal 5-HT-2A receptor finding associated with evidence of increased extracellular 5-HT. Increased 2A finding and decreased extracellular 5-HT will occur in ill AN and BN subjects.
In Aim 2 150 PET imaging and 11-C-WAY100635 studies will assess 5-HT-1A receptor binding. Knockout gene studies in mice support the hypothesis that a malfunction of pre-synaptic raphe autoreceptors could contribute to increased 5-HT activity and behavioral symptoms. Thus, 1A binding may not change with state of the illness.
Aim 3 will test whether core AN or BN symptoms or impulse control are related to 5-HT neuronal activity. To fully characterize the 14 or more receptors and other components of the 5-HT neuronal pathways may require multiple ligands. In the long term (years 3 to 5) the candidate seeks to use this K05 to develop a multicenter collaborative study to 1) use PET imaging and radioligands to comprehensively characterize 5-HT and related systems in AN and BN and 2) develop rodent models relating 5-HT to behavior. In addition, this K05 award will support training the candidate, who in turn will train established and young investigators in these new technologies. Understanding whether biologic vulnerabilities, such as a 5-HT disturbance, occurs in AN and BN may contribute to developing a new treatment interventions for these often chronic and deadly disorders as well as shed light on the relation of 5-HT neurotransmission and behavior.
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