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.

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Rationale: GABA A receptors containing the α5 subunit (i.e., α5GABA A ) appear to be critically involved in the reinforcing and subjective effects of alcohol. Their role in alcohol relapse remains unknown.Objectives: Pharmacological approaches were used to probe the role of α5GABA A receptors in alcohol seeking induced by re-exposure to an sweetened alcohol-paired cue, as well as in alcohol +sucrose vs. sucrose self-administration. Methods:For reinstatement studies, rats were trained to self-administer alcohol under a fixedratio schedule in which responding was maintained by alcohol+sucrose deliveries and an alcoholpaired stimulus. Sweetened alcohol seeking was extinguished by eliminating solution deliveries and the sweetened alcohol-paired stimulus. During reinstatement tests, animals received pretreatments of an α5GABA A inverse agonist (L-655,708) or an agonist (QH-ii-066) prior to sessions in which presentation of the sweetened alcohol-paired stimulus was restored, but no solution was delivered. For self-administration studies, rats were trained to self-administer alcohol +sucrose or sucrose under a fixed-ratio schedule. Once stable, animals received pretreatments of QH-ii-066, L-655,708, the inverse agonist RY-023 or naltrexone.Results: L-655,708 attenuated reinstatement of sweetened alcohol seeking by alcohol+sucrosepaired cues; whereas sweetened alcohol-seeking behavior was augmented by QH-ii-066, albeit at different doses in different rats. Both L-655,708 and RY-023 selectively reduced alcohol+sucrose vs. sucrose self-administration. In contrast, naltrexone reduced both alcohol+sucrose and sucrose self-administration; whereas QH-ii-066 enhanced sucrose self-administration only.

Ethanol's reinforcing and subjective effects, as well as its ability to induce relapse, are powerful factors contributing to its widespread use and abuse. A significant mediator of these behavioral effects is the GABA receptor system. GABA receptors are the target for γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS. Structurally, they are pentameric, transmembrane chloride ion channels comprised of subunits from at least eight different families of distinct proteins. The contribution of different GABA subunits to ethanol's diverse abuse-related effects is not clear and remains an area of research focus. This chapter details the clinical and preclinical findings supporting roles for different α, β, γ, and δ subunit-containing GABA receptors in ethanol's reinforcing, subjective/discriminative stimulus, and relapse-inducing effects. The reinforcing properties of ethanol have been studied the most systematically, and convergent preclinical evidence suggests a key role for the α5 subunit in those effects. Regarding ethanol's subjective/discriminative stimulus effects, clinical and genetic findings support a primary role for the α2 subunit, whereas preclinical evidence implicates the α5 subunit. At present, too few studies investigating ethanol relapse exist to make any solid conclusions regarding the role of specific GABA subunits in this abuse-related effect.

Humans with histories of prolonged heavy alcohol use exhibit poorer performance on cognitive tasks associated with problem solving, short-term memory, and visuospatial reasoning, even following the cessation of drinking, when compared with healthy controls. It is unclear, however, whether the cognitive problems are a consequence of alcohol exposure or a contributing factor to alcohol-use disorders. Here, we examined the relationship between performance on a novel object recognition (NOR) task and total alcohol consumption (TAC) in adult male rhesus macaques (n = 12; ETH group; trained to self-administer alcohol). NOR performance in this group was assessed prior to induction of alcohol drinking (“pre”) and, again, after a 1-year abstinence period (“post”) and was compared to the performance of a second group (n = 6; Control group), which was alcohol-naïve. In the NOR task, difficulty was manipulated across three phases by varying specific object features and/or by varying duration of access to objects. For each monkey, we measured aspects of novelty-related behavior including novelty detection, novelty reactivity, and perseverative behavior. TAC during induction and a “free” access period in which the monkey could choose between water and a 4% w/v ethanol solution also was determined. We found that performance deficits in the NOR task were a consequence of high total alcohol intake instead of a predictor of subsequent high intake. Poor NOR performance in drinkers with the highest intakes was characterized by increased perseverative behavior rather than an inability to detect or react to novelty. Finally, the observed deficits are long-lasting – persisting even after a year of abstinence. Given the prevalent and persistent nature of alcohol-induced cognitive deficits in patients in treatment settings, understanding the nature of the deficit and its neural basis could ultimately offer novel treatment approaches based on the reversal of alcohol-induced impairment.

Resurgence may be a mechanism of relapse in alcohol-use disorder (AUD) patients upon discharge from treatment as part of an abuse-treatment-relapse cycle. Adjunctive pharmacotherapies may be a means to facilitate behavioral treatments and block resurgence. Experiments were conducted using a model of alcohol self-administration to assess the repeatability of the elimination and resurgence of alcohol-maintained behavior, and the effects of naltrexone. Experiments had three phases. In Phase 1, behavior was maintained by oral alcohol under a fixed-ratio schedule. In Phase 2, behavior was extinguished and condensed milk was delivered under a differentialreinforcement-of-other-behavior (DRO) schedule. In Phase 3, the DRO schedule was eliminated. In Experiment 1, this 3-phase cycle was replicated four times. Across replications, response rates and dose of alcohol consumed did not differ in Phase 1, alcohol-maintained behavior was eliminated more rapidly in Phase 2, and the resurgence effect was generally stable in Phase 3. In Experiment 2, naltrexone was administered in Phase 2, Phase 3, or both Phases 2 and 3, to different groups of rats. Naltrexone facilitated the elimination of alcohol-maintained behavior in Phase 2 and, the resurgence of alcohol-maintained behavior was reduced only for those rats that received naltrexone in both Phases. Together, these experiments demonstrate that the resurgence of alcohol-maintained behavior is replicable within-subjects and, further, resurgence of alcoholmaintained behavior may be a useful model to evaluate pharmacological interventions to facilitate behavioral treatments and reduce the likelihood of relapse. Results with naltrexone support the use of medication-assisted therapy approaches to reduce relapse risk in patients. Keywordsrelapse; resurgence; alcohol; alcohol use disorder; pharmacotherapy Alcohol use disorder (AUD) affects approximately 15.1 million adults in the United States (Substance Abuse and Mental Health Services Administration, 2015) and, fortunately, there are several treatment options available for patients. Behavioral therapies based upon the use of alternative reinforcers, such as contingency management (Davis, Kurti, Skelly, Redner,