غلظت گلوتامات مایع مغزی نخاعی مرتبط با خشونت تکانشی در افراد

Neurochemical studies have pointed to a modulatory role in human aggression for various central neurotransmitters. Some (e.g., serotonin) appear to play an inhibitory role, while others appear to play a facilitator role. While recent animal studies of glutaminergic activity suggest a facilitator role for central glutamate in the modulation of aggression, no human studies of central glutaminergic indices have yet been reported regarding aggression. Basal lumbar cerebrospinal fluid (CSF) was obtained from 38 physically healthy subjects with DSM-IV Personality Disorder (PD: n = 28) and from Healthy Volunteers (HV: n = 10) and assayed for glutamate, and other neurotransmitters, in CSF and correlated with measures of aggression and impulsivity. CSF Glutamate levels did not differ between the PD and HC subjects but did directly correlate with composite measures of both aggression and impulsivity and a composite measure of impulsive aggression in both groups. These data suggest a positive relationship between CSF Glutamate levels and measures of impulsive aggression in human subjects. Thus, glutamate function may contribute to the complex central neuromodulation of impulsive aggression in human subjects.

Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system (Niciu et al., 2012). Glutamate is stored in vesicles at chemical synapses where nerve impulses trigger release of glutamate from the pre-synaptic neuron onto post-synaptic glutamate receptors such as the ionotropic NMDA and AMPA/Kainate receptors and the G-protein coupled metabotropic glutamate receptors. Glutamate plays an important role in brain synaptic plasticity and is involved in a number of cognitive functions including learning and memory in the hippocampus, neocortex, and other brain regions. Glutamate has been implicated to play a role in a variety of neuropsychiatric disorders including schizophrenia (Lin et al., 2012), mood disorder (Machado-Vieira et al., 2012), anxiety disorders (Riaza Bermudo-Soriano et al., 2012), addictive disorders (Olive et al., 2012), and other neuropsychiatric disorders (e.g., Hu et al., 2012; Carlson, 2012). While little work has been reported on the role of glutamate in human aggressive behavior, preclinical studies suggest that stimulation of central glutamate receptors typically increases aggressive behavior in lower mammals. As demonstrated in a number of preclinical studies in rodents, an excitatory amino acid pathway from the medial hypothalamus (MH) to the periaqueductal gray (PAG) is associated with aggressive behavior (Beart et al., 1998, 1990; Beitz, 1989). In the rat, there is a dense and distinct group of glutamatergic neurons expressing glutamate transporter protein over the entire hypothalamic attack area, with the rostral portion predominantly containing glutamatergic, and the caudal portion having both glutaminergic and, to a lesser degree, GABAergic, neurons (Hrabovszky et al., 2005). Microinjections of glutamate into the cat PAG elicit defensive rage (Bandler, 1984), a finding consistent with the release of glutamate by MH neurons and the activation of PAG neurons in the expression of defensive rage in the cat. This was confirmed in subsequent studies demonstrating that pretreatment with the glutamate antagonist kynurenic acid blocked MH facilitation of PAG elicited defensive rage, and that NMDA injected into PAG defensive rage sites facilitated the rage response elicited from that site (Lu et al., 1992). Administration of an NMDA receptor antagonist into the PAG blocked MH facilitation of PAG-elicited defensive rage. The antagonist dose-dependently suppressed defensive rage elicited by stimulation of the MH (Schubert et al., 1996). This study also reported that a considerable number of glutamate neurons within the anteromedial hypothalamus project to PAG defensive rage sites (Schubert et al., 1996). Excitatory inputs from the basal amygdala also project to the PAG and there is evidence for PAG NMDA receptor mediated defensive rage following their stimulation (Shaikh et al., 1994); basal amygdaloid neurons projecting to PAG defensive rage sites also stain immunopositive for glutamate. In addition, mice bred for reduction of function in the NMDA R1 subunit display an absence of species-typical fighting in the resident intruder model of aggression (Duncan et al., 2004). Preclinical studies of the other ionotropic glutamate receptor, AMPA, and as well as metabotropic glutamate receptors support a glutamate hypothesis of aggressive behavior. For example, mice deficient for the AMPA receptor GluR-A1 subunit are less aggressive than their wild-type counterparts (Vekovischeva et al., 2004) and treatment with AMPA receptor antagonists also reduces aggression in aggressive mice strains (Vekovischeva et al., 2007). Knockout of the GluA3-AMPA receptor subunit in mice is associated with a reduction in aggressive behavior (Adamczyk et al., 2012). In addition, genome-wide scans to identify aggression quantitative trait loci in aggressive mice strains find that the Gria3 gene, which encodes for a subunit of the AMPA3 receptor, accounts for the strain differences in aggressive behavior in the resident-intruder mouse model of aggression (Brodkin et al., 2002). Finally, selective mGlu-1 (Navarro et al., 2008) and mGlu-5 (Navarro et al., 2006), receptor blockade reduce aggression in mice models of aggression (Navarro et al., 2006). In contrast, agonist stimulation of auto-inhibitory mGlu-2/3 (Ago et al., 2012) or mGlu-7 (Navarro et al., 2009) receptors reduces aggression in mice. Given the results of these various preclinical studies, we sought to explore if cerebrospinal fluid (CSF) Glutamate would be associated with aggression and/or impulsivity in personality disordered and healthy volunteer subjects. We hypothesized that CSF Glutamate would correlate directly with measures of aggression and/or impulsivity.

Demographic characteristics for the HV and PD subjects are displayed in Table 1. These groups did not differ in the distribution of gender or race or in age, height, weight, or in Hollinghead's socioeconomic score. However, multiple regression of raw CSF Glutamate levels, as dependent variable, and age, gender, race, SES, height and weight as independent variables, revealed a nearly significant relationship between raw CSF Glutamate levels and these demographic/physical variables (R = .56, R2 = .18, F[6,31] = 2.33, p = .057). Accordingly, all analyses employed the residual value for the CSF Glutamate level after the removal of the variance associated with these variables. As expected, HV and PD subjects differed significantly in Aggression (BDHI), Impulsivity (BIS-11), and in GAF scores.