This is a Resubmission of a Competitive Renewal Application of NIMH Grant R01-MH46948. During the current grant period, the presence of a relationship between impulsive aggressive/suicidal behavior and selected indices of 5-HT function (e.g., PRL response to d-Fenfluramine (d-FEN) Challenge) in personality disordered subjects was confirmed. Despite this, neuropharmacologic nature of these relationships is unclear. Little is known about the specific role that various 5-HT receptor subtype systems play in mediating aggressive and/or suicidal behavior. While 5-HT antagonist studies suggest that the PRL response to d-FEN reflects activation of post-synaptic 5-HT-2a/2c receptors, little is known about the role of central 5-HT-1a receptors in human aggression. A role for 5-HT-1a receptors in aggression is suggested by the potent antiaggressive effects of 5-HT-1a agonists in animal studies and by preliminary data showing inverse relationships between aggression and the hormonal responses to 5-HT-1a agents. In addition, only limited data is available regarding the role of central noradrenergic (NE) systems in human aggression. A role for central NE systems is suggested by animal studies and limited neurochemical/pharmaco-challenge studies in psychiatric patients. In contrast to 5-HT, the NE system has a direct relationship with aggression. Since the NE system plays a critical role in the detection of novel (aversive) stimuli, the PI hypothesizes that sensitivity to aversive stimuli (e.g., irritability) plays a role on setting the threshold at which aversive stimuli are detected and lead to a behavioral response which can be aggressive in nature. Accordingly, the PI wishes to extend his biological studies of impulsive aggressive/suicidal behavior in personality disordered subjects, and healthy volunteers, to include an examination of the limbic-hypothalamic systems involving 5-HT-1a (Ipsapirone Challenge) and alpha-2 NE (Clonidine Challenge) receptors. Simultaneous evaluation of the limbic-hypothalamic 5-HT-2a/2c system with d-FEN Challenge will allow a comprehensive assessment of these three potentially important central neuronal systems in aggressive/suicidal behavior in human subjects. Impulsive aggressive behavior will be comprehensively assessed through the use of self-report, historical, and direct laboratory indices of aggression.
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