Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH046948-09
Application #
2890440
Study Section
Special Emphasis Panel (ZMH1-NRB-L (M2))
Program Officer
Meinecke, Douglas L
Project Start
1991-04-01
Project End
1999-08-31
Budget Start
1999-05-01
Budget End
1999-08-31
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Mcp Hahnemann University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19102

  Publications

Puhalla, Alexander A; McCloskey, Michael S; Brickman, Lauren J et al. (2016) Defense styles in Intermittent Explosive Disorder. Psychiatry Res 238:137-142
Fanning, Jennifer R; Meyerhoff, Jonah J; Lee, Royce et al. (2014) History of childhood maltreatment in intermittent explosive disorder and suicidal behavior. J Psychiatr Res 56:10-7
Fettich, Karla C; McCloskey, Michael S; Look, Amy E et al. (2014) Emotion regulation deficits in intermittent explosive disorder. Aggress Behav :
Marseille, Robert; Lee, Royce; Coccaro, Emil F (2012) Inter-relationship between different platelet measures of 5-HT and their relationship to aggression in human subjects. Prog Neuropsychopharmacol Biol Psychiatry 36:277-81
Coccaro, Emil F (2011) Intermittent explosive disorder: development of integrated research criteria for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Compr Psychiatry 52:119-25
Dakwar, Elias; Popii, Marias; Coccaro, Emil F (2011) Lifetime history of cigarette smoking associated with aggression and impulsivity in both healthy and personality disordered volunteers. J Pers Disord 25:645-55
Coccaro, Emil F; Lee, Royce; Kavoussi, Richard J (2010) Inverse relationship between numbers of 5-HT transporter binding sites and life history of aggression and intermittent explosive disorder. J Psychiatr Res 44:137-42
Almeida, Marcela; Lee, Royce; Coccaro, Emil F (2010) Cortisol responses to ipsapirone challenge correlate with aggression, while basal cortisol levels correlate with impulsivity, in personality disorder and healthy volunteer subjects. J Psychiatr Res 44:874-80
Lee, Royce; Coccaro, Emil F (2010) Plasma homovanillic acid correlates inversely with history of childhood trauma in personality disordered and healthy control adults. J Neural Transm (Vienna) 117:1327-34
Coccaro, Emil F; Lee, Royce; Kavoussi, Richard J (2010) Aggression, suicidality, and intermittent explosive disorder: serotonergic correlates in personality disorder and healthy control subjects. Neuropsychopharmacology 35:435-44

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