35 Furthermore, in this study as well, correlations between amygdala and anterior cingulate were disrupted in the aggressive BPD patients compared with controls.36 Finally, reductions in serotonin transporter (5-HTT) binding appear to be associated with impulsive aggression in BPD patients.37 These data are consistent with reduced

serotonergic facilitation via 5-HT2a receptors of prefrontal cortical inhibitory regions, Inhibitors,research,lifescience,medical particularly anterior cingulate and orbital frontal cortex, which serve to “brake” the amygdala. Thus, reduced serotonergic activity may result in disinhibited aggression generated in response Inhibitors,research,lifescience,medical to negatively evaluated stimuli. This pathophysiological model could in part emerge from alterations in serotonergic activity, primarily reduced integrity of prefrontal inhibitory centers, or exaggerated responsiveness of amygdala and

related limbic ATM Kinase Inhibitor molecular weight structures. Endophenotypes that reflect reduced serotonergic activity, altered frontal activation, or enhanced limbic reactivity thus might serve to characterize specific vulnerabilities of this functional circuitry in aggressive personality disorder patients. They also may be used in family studies to characterize relatives or in Inhibitors,research,lifescience,medical conjunction with candidate genes, for example, in the serotonergic system, in association studies. Thus, for example, a polymorphism in the serotonin transporter that determines the amount of transporter expressed has been associated with neuroticism,38 and aggression in some

studies,39,40 but not in others.41 The s allele is associated with impulsivity Inhibitors,research,lifescience,medical and BPD in bulimic patients,42 aggression and violent suicide attempts in schizophrenic patients,43,44 aggression in cocaine abusers,45 and aggression and suicide in alcoholics,46,47 and also with a potential Inhibitors,research,lifescience,medical intermediate phenotype of aggression, the blunted prolactin response to fenfluramine.48 The polymorphism for tryptophan hydroxylase was reported to be associated with aggression in one pilot study,40 and with self -harm in another.49 A more recent study suggested association between the 5-HTR1B receptor in suicide history50 and recent data suggest the possibility of a 5-HT2a receptor polymorphism being associated with PD184352 (CI-1040) self -injurious behavior (New, personal communication). These studies illustrate how a dimensional approach might generate intermediate clinical variables or phenotypes to identify candidate genes of interest. Studies are underway to evaluate more objective laboratory evaluations in relation to these genetypes, such as the PSAP and potentially more biologically based “endo”-phenotypes based on neuroimaging studies.