Our social lexicon includes numerous phrases to describe how individuals behave under the influence of alcohol. In particular, people often refer to ‘sad drunks,’ ‘happy drunks,’ and to ‘angry drunks.’ These descriptions illustrate that we intuitively recognize the large variation across the population in how individuals behave under the influence of alcohol. Moreover, the tendency for alcohol to elicit anger and aggression in some individuals is particularly problematic in our society, as up to 50% of violence-related injuries in the world involve the use of alcohol (Cherpitel et al, 2012). Therefore, increased understanding of the neurobiological underpinnings of why some individuals develop alcohol-heightened aggression could lead to targeted behavioral or pharmacological approaches to drastically reduce violence in our society. Intriguingly, individual variation in the behavioral response to alcohol is not limited to humans. Indeed, mice, rats, and monkeys can all exhibit alcohol-heightened aggression, and, as with humans, this form of aggression is only observed in a small subset of the population (van Erp and Miczek, 1997; Miczek et al, 1998). Thus, it is possible to use animal models to determine what biological factors cause some individuals to become violent under the influence of alcohol, providing a means for developing preventative strategies.

In this issue of Neuropsychopharmacology, Newman et al (2018) took advantage of individual differences in the expression of alcohol-heightened aggression in mice to identify novel mechanisms underlying this behavioral vulnerability. The experiments focused on determining if alcohol-heightened aggressor mice (AHAs) differed from alcohol non-heightened aggressor mice (ANAs) in their expression of glutamatergic NMDA receptor subunits and their behavioral response to NMDAR inhibition. Alcohol has diverse effects on the central nervous system, however, inhibition of NMDAR signaling is thought to be involved in many of the behavioral manifestations of alcohol intoxication (Morisot and Ron, 2017). Therefore, differential sensitivity or function of NMDA receptors could explain individual variation in alcohol-heightened aggression. Specifically, NMDARs in the prefrontal cortex (PFC) are located on both GABAergic interneurons and pyramidal cells, and Newman and colleagues hypothesized that the balance of NMDAR-mediated inhibition vs disinhibition of the PFC could regulate individual differences in the expression of aggressive behavior.

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