Neuroimmune signaling in alcohol use disorder

Abstract

Alcohol use disorder (AUD) is a widespread disease with limited treatment options. Targeting the neuroimmune system is a new avenue for developing or repurposing effective pharmacotherapies. Alcohol modulates innate immune signaling in different cell types in the brain by altering gene expression and the molecular pathways that regulate neuroinflammation. Chronic alcohol abuse may cause an imbalance in neuroimmune function, resulting in prolonged perturbations in brain function. Likewise, manipulating the neuroimmune system may change alcohol-related behaviors. Psychiatric disorders that are comorbid with AUD, such as post-traumatic stress disorder, major depressive disorder, and other substance use disorders, may also have underlying neuroimmune mechanisms; current evidence suggests that convergent immune pathways may be involved in AUD and in these comorbid disorders. In this review, we provide an overview of major neuroimmune cell-types and pathways involved in mediating alcohol behaviors, discuss potential mechanisms of alcohol-induced neuroimmune activation, and present recent clinical evidence for candidate immune-related drugs to treat AUD.

Keywords: Addiction; Alcohol; Astrocyte; Comorbidity; Microglia; Neuroimmune.

Fig. 1.

Microglia-specific consequences of alcohol-induced neuroinflammation. Alcohol exposure generates a proinflammatory environment in brain, resulting in up-regulation of immune ligands such as cytokines and chemokines. This results in activation of immune receptors on microglia, persistent transcriptome changes, structural plasticity, and the production of several inflammatory mediators that can alter neuronal function.

Fig. 2.

Astrocyte-specific consequences of alcohol-induced neuroinflammation. Alcohol exposure generates a proinflammatory environment in brain, resulting in up-regulation of immune ligands such as cytokines and chemokines. This results in activation of immune receptors on astrocytes, leading to transcriptome changes which contribute to the modulation of several astrocyte functions, including glutamate homeostasis, calcium signaling, gap junction communication, structural plasticity, and the production of inflammatory mediators, which can alter neuronal function in various ways.

Fig. 3.

Potential neuroimmune-mediated mechanisms that underlie associations between psychiatric diseases including alcohol use disorder (AUD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). AUD, MDD, and PTSD are frequently comorbid. Environmental and biological factors that can influence and lead to neuroinflammation are associated with all three disorders. Sustained neuroimmune imbalance can lead to physiological consequences that drive behavioural phenotypes associated with psychiatric disease. Altered behavior may enhance further risk for neuroinflammation, resulting in a persistent cycle that leaves patients vulnerable to additional psychiatric disorders. Pharmacotherapies that target neuroinflammation are possible treatment options for comorbid psychiatric diseases with common neuroimmune elements.