A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression

Abstract

Alcohol is associated with nearly half of all violent crimes committed in the United States; yet, a potential neural basis for this type of pathological aggression remains elusive. Alcohol may act on N-methyl-d-aspartate receptors (NMDARs) within cortical circuits to impede processing and to promote aggression. Here, male mice were characterized as alcohol-heightened (AHAs) or alcohol non-heightened aggressors (ANAs) during resident-intruder confrontations after self-administering 1.0 g/kg alcohol (6% w/v) or water. Alcohol produced a pathological-like pattern of aggression in AHAs; these mice shifted their bites to more vulnerable locations on the body of a submissive animal, including the anterior back and ventrum after consuming alcohol. In addition, through immunoblotting, we found that AHAs overexpressed the NMDAR GluN2D subunit in the prefrontal cortex (PFC) as compared to ANAs while the two phenotypes expressed similar levels of GluN1, GluN2A and GluN2B. After identifying several behavioral and molecular characteristics that distinguish AHAs from ANAs, we tested additional mice for their aggression following preferential antagonism of GluN2D-containing NMDARs. In these experiments, groups of AHAs and ANAs self-administered 1.0 g/kg alcohol (6% w/v) or water before receiving intraperitoneal (i.p.) doses of ketamine or memantine, or infusions of memantine directly into the prelimbic (PLmPFC) or infralimbic medial PFC (ILmPFC). Moderate doses of IP ketamine, IP memantine, or intra-PLmPFC memantine increased aggression in AHAs, but only in the absence of alcohol. Prior alcohol intake blocked the pro-aggressive effects of ketamine or memantine. In contrast, only memantine, administered systemically or intra-PLmPFC, interacted with prior alcohol intake to escalate aggression in ANAs. Intra-ILmPFC memantine had no effect on aggression in either AHAs or ANAs. In sum, this work illustrates a potential role of GluN2D-containing NMDARs in the PLmPFC in alcohol-heightened aggression. GluN2D-containing NMDARs are highly expressed on cortical parvalbumin-containing interneurons, suggesting that, in a subset of individuals, alcohol may functionally alter signal integration within cortical microcircuits to dysregulate threat reactivity and promote aggression. This work suggests that targeting GluN2D-NMDARs may be of use in reducing the impact of alcohol-related violence in the human population.

Ethanol as a stimulus to risky and auto-aggressive behaviour

“…The results are in favour of a better prognosis and lower mortality rates among people with isolated head injuries [8][9][10][11][12][13] sustained after the consumption of ethanol, compared to sober people, although the severity of such injuries tended to be higher. However, this "neuroprotective"effect of ethanol is observed only in single doses of ethanol, which This is can be explained by the inhibition of glutamatergic NMDA receptor activity in the CNS [14,15]. Like most NMDA receptor antagonists, ethanol consumed chronically is a neurotoxin [14,15,16,17].…”

“…However, this "neuroprotective"effect of ethanol is observed only in single doses of ethanol, which This is can be explained by the inhibition of glutamatergic NMDA receptor activity in the CNS [14,15]. Like most NMDA receptor antagonists, ethanol consumed chronically is a neurotoxin [14,15,16,17].…”

The Urge to Fight: Persistent Escalation by Alcohol and Role of NMDA Receptors in Mice

“…The 1.0 g/kg dose of alcohol was selective for FI response rate (i.e., aggressive motivation), and did not differentially affect aggressive performance, or locomotor behavior, in mice with or without a history of receiving daily alcohol treatments ( Table 2 and Figure 6 ). Excitatory and inhibitory amino acid regulatory elements in somatic and terminal regions of the DA motive system ( Volkow et al, 2017 ) are promising targets for escalated alcohol drinking and alcohol-heightened aggression ( Gourley et al, 2005 ; Takahashi et al, 2010 , 2015 ; Newman et al, 2012 , 2018 ). Thus, we examined the general role of iGluRs during later challenges with alcohol in mice that were historically treated with alcohol (2.2 g/kg) or water for 7 days.…”

“…These same mice significantly reduced their aggressive performance. Because the effects of alcohol and dizocilpine on these behavioral measures were diametrically opposed, it is likely that alcohol suppresses fighting in alcohol-naive animals through a non-glutamatergic mechanism, perhaps by positively modulating GABA A receptor activity ( Ticku and Kulkarni, 1988 ) rather than through a direct and synergistic inhibition of NMDA receptors – the later would be expected to increase fighting ( Newman et al, 2018 ). Unlike dizocilpine, ketamine did not increase FI responding in alcohol-naive mice, which may result from differences in drug kinetics or its interactions with alcohol ( Petrakis et al, 2004 ; Wai et al, 2013 ).…”

“…We hypothesized that during repeated exposures to alcohol, tolerance first develops to the sedative effects, and eventually sensitized responding emerges, which may serve as an index of motivation. We determined whether or not changes in the motivation to initiate aggressive acts occur with, or without, shifts in the intensity of fighting behavior ( Newman et al, 2018 ). Responding under the control of the FI schedule of reinforcement is a highly sensitive measure of appetitive behavior, indicating that the pattern of responding (i.e., the “scallop”) during successive administrations of alcohol may therefore be attributed to underlying changes in incentive-motivation.…”