The Neuroimmune Basis of Excessive Alcohol Consumption

The interplay between brain, behavior, and immune responses in the etiology and progression of alcohol abuse is a paradigm-shifting direction in addiction research that has transformed therapeutic outlook for alcohol use disorders (AUDs). Alcohol is thought to increase neuroimmune-related gene and protein expression through (i) gut-derived microbial products that activate innate immune cells, causing systemic induction of proinflammatory cytokines that are transported from blood to brain, as well as (ii) direct actions in the brain, where cross talk among neurons, glia, and other cells contributes to the release and signaling of immune molecules with inflammatory and neuromodulatory properties (Crews and Vetreno, 2016).

Interest in the alcohol-neuroimmune field was fueled by gene expression studies showing strong representation of immune- and inflammatory-related genes in brains from human alcoholics and rodents exposed to chronic alcohol (Liu et al, 2006; Robinson et al, 2014). Deletion of chemokines and other immune genes reduced alcohol drinking in mice and provided corroborating behavioral validation for several immune mediators that were predicted by the genomic studies (Blednov et al, 2012; Robinson et al, 2014). In contrast, immune activation by lipopolysaccharide (LPS) produced prolonged increases in alcohol consumption in mice, and treatment with either LPS or chronic intermittent alcohol produced overlapping changes in mouse brain transcriptomes (Robinson et al, 2014). The LPS-induced escalation in drinking may be related to persistent activation of immune genes in the brain that are also induced by chronic alcohol exposure.

It has been hypothesized that positive feedback cycles of proinflammatory peripheral-central immune signaling promote excessive alcohol drinking. In support of this, alcohol craving and consumption were positively correlated with elevated plasma levels of inflammatory cytokines in human alcoholics (Leclercq et al, 2014). Centrally, expression of innate immune molecules (eg, HMGB1, TLRs, and RAGE) increased in the brains of alcoholics and alcohol-exposed rodent models, and immune marker expression in humans was correlated with total lifetime alcohol consumption and age of drinking onset (Crews and Vetreno, 2016). Neuroimmune signaling has also been associated with synaptic remodeling and epigenetic changes induced by intermittent alcohol exposure in adolescent brain (Montesinos et al, 2016), where persistent synaptic and molecular changes during development may increase susceptibility to AUDs.

Investigating the genomics and pharmacology of neuroimmune pathways in chronic alcohol consumption is currently a goal for NIAAA, underscoring the impact of this area on research initiatives. Another priority is the use of novel computational resources that connect gene networks with potential therapeutic compounds. If alcohol causes genetic changes and neuroadaptations in immune pathways that are conserved across species (including humans), then cross-species brain genomic datasets and computational approaches could be used to link alcohol-related patterns in gene coexpression with investigational or FDA-approved drugs that can normalize the networks and reduce drinking. The ‘gene network to pharmacotherapy' approach, together with behavioral validation of identified targets in animal models and alcoholics, aims to link specific neuroimmune pathways to addiction vulnerability and fast-track treatment strategies for AUDs. The accumulating evidence for alcohol-neuroimmune signaling, together with emerging computational tools, is forging a revolutionary course for addiction research with renewed impetus and expectation for positive therapeutic outcome.

Funding and disclosure

This research is supported by funding through the National Institute on Alcohol Abuse and Alcoholism and the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune): U01 AA013520 and R01 AA012404. The authors declare no conflict of interest.