Human aggression constitutes a multidetermined act which often results in physical (or verbal) assault to others or self (or objects) as the end product. It appears in several forms and may be defensive, premeditated (e.g., predatory) or impulsive (e.g., irritable), in nature. Research into the etioogic determinants of premeditated and impulsive human aggression have focused on variojs sociologic, psuchologic, and biogenetic factors. Among these, the most consistent biogenetic factor associated with impulsive (but not premeditated) aggression is a reduction in the activity of the central monoamine neurotransmitter serotonin (5-HT). 5-HT's role in the regulation of impulsive aggressive behavior is thought to arise from its role in neuronal inhibition, through which it raises the threshold for action in response to an outward (or inward) stimulus. In this formulation, 5-HT acts to restrain the individual from assaulting the object of stimulus. Empirically, a role for central 5-HT in the regultion of impulsive aggression and/or suicidal (i.e., of a violent and/or impulsive nature) behavior in humans is suggested by the association of reductions in indices of central 5-HT activity (e.g. brain 5-HT/5-HIAA; lumbar CSF 5-HIAA; neuroendocrine responses to 5-HT agents) in psychiatric patients with prominent histories of impulsive aggressive and suicidal behavior, particularly patients with DSM-III-R personality disorders. In this RSDA (Level II) Application, the principal investigator proposes to conduct sysematic studies regarding the relationship between indices of central 5-HT function (i.e., CSF 5-HIAA concentration and prolactin response to d-Fenfluramine Challenge) and indices of impulsive aggressive and suicidal behaviors in personality disorder patients of both genders in order to test the hypothesis that central 5-HT function and these behaviors are inversely related. Family studies will also be conducted in order to test the hypotheseis that indices of reduced central 5-HT function in these patients are also correlated with a increased morrid risk of these behaviors in their first-degree biological relatives. Studies investigating the intra-individual stability, and the 5-HT receptor subtype components, of the PRL response to d-Fenfluramine Challenge will also be conducted in order to est the adequacy of this index as a """"""""trait"""""""" marker of central 5-HT function and to elucidate the 5-HT receptor subtype possibly associated with impulsive aggression in these patients. Finally, a double-blind, placebo-controlled, treatment trial of the 5-HT uptake inhibitor, Fluoxetine, will be conducted in patients with prominent histories of impulsive aggression in order to experimentally test the hypothesis that enhancement of central 5-HT function will be correlated with this response to central 5-HT targeted pharmacologic treatment.
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