Primed for addiction: A critical review of the role of microglia in the neurodevelopmental consequences of adolescent alcohol drinking

Abstract

Alcohol is one of the most widely used recreational substances worldwide, with drinking frequently initiated during adolescence. The developmental state of the adolescent brain makes it vulnerable to initiating alcohol use, often in high doses, and particularly susceptible to alcohol‐induced brain changes. Microglia, the brain parenchymal macrophages, have been implicated in mediating some of these effects, though the role that these cells play in the progression from alcohol drinking to dependence remains unclear. Microglia are uniquely positioned to sense and respond to central nervous system insult, and are now understood to exhibit innate immune memory, or “priming,” altering their future functional responses based on prior exposures. In alcohol use disorders (AUDs), the role of microglia is debated. Whereas microglial activation can be pathogenic, contributing to neuroinflammation, tissue damage, and behavioral changes, or protective, it can also engage protective functions, providing support and mediating the resolution of damage. Understanding the role of microglia in adolescent AUDs is complicated by the fact that microglia are thought to be involved in developmental processes such as synaptic refinement and myelination, which underlie the functional maturation of multiple brain systems in adolescence. Thus, the role microglia play in the impact of alcohol use in adolescence is likely multifaceted. Long‐term sequelae may be due to a failure to recover from EtOH‐induced tissue damage, altered neurodevelopmental trajectories, and/or persistent changes to microglial responsivity and function. Here, we review critically the literature surrounding the effects of alcohol on microglia in models of adolescent alcohol misuse. We attempt to disentangle what is known about microglia from other neuroimmune effectors, to which we apply recent discoveries on the role of microglia in development and plasticity. Considered altogether, these studies challenge assumptions that proinflammatory microglia drive addiction. Alcohol priming microglia and thereby perturbing their homeostatic roles in neurodevelopment, especially during critical periods of plasticity such as adolescence, may have more serious implications for the neuropathogenesis of AUDs in adolescents.

Adolescent brain maturation and the neuropathological effects of binge drinking: A critical review

“…In their experiment, pro-inflammatory markers such as IL-1β and TNFα were only increased in alcohol-exposed male rats suggesting a sex-dependent differential immune-responsivity to alcohol in adolescence. There are a growing number of pre-clinical studies emerging that support a role for alcohol-induced astrocyte and microglia activation, imbalance of reactive oxygen species, and pro-inflammatory signaling ( Crews and Nixon, 2009 ; Alfonso-Loeches et al, 2012 ; Risher et al, 2015b ; Vetreno and Crews, 2015 ; McClintick et al, 2018 ; Melbourne et al, 2021 ; Peng and Nixon, 2021 ). Based on these findings, it would be interesting to determine if targeting these non-neuronal cells and related pro-inflammatory signaling pathways is an effective approach to preventing alcohol-induced neuronal cell death.…”

Sensitivity to the initial rewarding effects of alcohol: Influence of age, sex, and β‐endorphin

“…Adolescence is a time of increased neuroplasticity as well as heightened sensitivity of the HPA neuroendocrine stress axis (Spear, 2009) and exposure to EtOH during development boosts the likelihood AUDs (Luciana & Collins, 2022; Melbourne et al., 2021). For example, adolescent binge drinking affects brain development to make disordered use during adulthood more likely (Kane et al., 2014).…”

“…Adolescence is a time of increased neuroplasticity as well as heightened sensitivity of the HPA neuroendocrine stress axis (Spear, 2009) and exposure to EtOH during development boosts the likelihood AUDs (Luciana & Collins, 2022;Melbourne et al, 2021).…”

Focal mu‐opioid receptor activation promotes neuroinflammation and microglial activation in the mesocorticolimbic system: Alterations induced by inflammatory pain

“…Nonetheless, very little is known of how the presence of a pain condition affects microglial activity within the different brain subareas. This is unfortunate since most of pain comorbidities, such as negative affect or drug use disorders, involve neuroplastic and neurochemical alterations in brain nuclei in which microglia play a pivotal role (Burkovetskaya et al, 2020;Cuitavi, Lorente, et al, 2021;Han et al, 2020;Jia et al, 2021;Melbourne et al, 2021;Taylor et al, 2015Taylor et al, , 2016).…”