Several lines of evidence have suggested that people who are ill with bulimia nervosa (BN) have disturbances of brain serotonin (5-HT) activity. Our last funding period found that alterations persisted after long-term recovery BN (i.e., elevated (p <.0001) CSF 5-HIAA, the main metabolite of 5-HT). The major aim of this competing renewal is to test the hypothesis that BN individuals have a trait-related disturbance of 5-HT neuronal modulation which contributes to erratic extremes of over-control and under-control, such as restricted eating and bingeing, which in turn, exacerbates 5HT dysfunction and dysphoric symptoms. In order to characterize the relationship of 5-HT and impulse dyscontrol, this 4-year study will investigate 2 subgroups of recovered BN (30 with and 30 without a lifetime history of multi-impulsive behaviors) and 30 matched control women. To avoid the confounding effects of malnutrition, we will @l study subjects who are long-term recovered from BN and who have no history of anorexia nervosa.
Aim 1 will characterize 5-HT function in recovered BN.
Aim 1 a will seek to replicate the finding of increased CSF 5HIAA in a larger and better defined sample, We postulate that, when recovered, BN individuals have increased 5-HT signal transmission (and behavioral over-control) due to a trait defect in 5-HT neuronal modulation.
Aim 1 b will contrast the effect on behavior when 5-HT is reduced (acute tryptophan depletion (ATD)) or increased (d-fenfluramine (d-FF)). Preliminary data suggests that ATD will cause dysphoric mood and bingeing as a result of reduced 5-HT behavioral inhibition, whereas d-FF will have little behavioral effect, because the 5-HT system is already at maximal output.
Aim 1 c will use [18F]altanserin, a 5-HT2A receptor antagonist, to assess 5-HT2A receptor binding on PET imaging studies. Preliminary data support our prediction that recovered BN will have reduced binding of [18F]altanserin and little change in [18F]altanserin binding after d-FF administration. We hypothesize that increased extracellular 5-HT competes with [18F]altanserin for binding to and/or down regulates post-synaptic receptors.
Aim 1 d will determine whether 5-HT candidate gene polymorphisms can be identified in BN.
Aim 2 is an exploratory aim to determine whether other neurotransmitter alterations persist after recovery, and if they contribute to psychopathology in BN. Preliminary data suggest a possible role for oxytocin in comorbid obsessions, vasopressin in Cluster B personality disorders, and CCK in anxiety/panic symptoms. Our long-term goal is to identify behavioral and biological phenotypes that characterize the vulnerabilities to develop BN, subtypes of BN, and contribute to comorbid disorders.
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