Considerable evidence suggests anorexia nervosa (AN) and bulimia nervosa (BN) have trait disturbances of brain serotonin (5-HT), which occur premorbidly; are exaggerated during the ill state; persist after recovery (REC); and contribute to behavior. In the last funding period, positron emission tomography (PET) with [18F]altanserin and [11C]WAY100635 radioligands showed ILL and REC AN/AN-BN had decreased 5-HT2A and increased 5-HT1A receptor activity, although alterations were less pronounced after REC.
AIM 1 seeks to understand 5-HT system response to fluoxetine treatment in AN as this medication is ineffective when ILL, but is useful in reducing symptoms after weight restoration. We predict fluoxetine will not shange 5-HT1A and 5-HT2A receptor activity in ILL AN/AN-BN. However, good response in REC AN/AN-BN will be associated with desensitized 5-HT1A autoreceptors and normalization of harm avoidance and limbic postsynaptic 5-HT1A and 5-HT2A receptor activity. Pre-medication PET [11C]WAY100635 and [tSF]altanserin studies will be done in 30 ILL and 30 REC AN/AN-BN women, and control women (CW) who are 18 to 45 years old. PET studies will be repeated on ILL and REC AN/AN-BN after 8 weeks of fluoxetine treatment.
AIM 2 will use AIM1 subjects to replicate and clarify to what degree 5-HT receptors and specific brain regions are related to disturbances shared by AN and BN, or which distinguish subtypes. For example, for 5-HT2A receptors, only AN have alterations in pregenual cingulate and mesial temporal regions, perhaps playing a role in emotional integration, whereas only BN have involvement of the orbital frontal cortex, perhaps related to impulse dyscontrol.
AIM 2 will investigate models of 5-HT1A and 5-HT2A receptor interactions, and relationships of 5-HT receptors to behavior, cognition, and age. Taste, smells, and foods are known to activate the regions (orbitalfrontal, anterior cingulate, antermedial temporal/amygdala) found to be involved in AN and BN. Our pilot data support evidence suggesting these region contribute to reward in feeding behavior.
AIM 3 will use a sucrose taste to test the hypothesis that feeding may elicit little reward in AN and exaggerated reward in BN as reflected by fMRI response. Groups of 25 REC AN, REC ANBN, REC BN and control women will be compared. Understanding biologic vulnerabilities in AN and BN may contribute to developing new treatment interventions for these often chronic and deadly disorders and shed light on 5HT activity and behavior. This is a resubmissien of a cemDetina renewal of MH46001.
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