Neuroinflammation, Glia-Neuron Crosstalk, and Energy Metabolism in Alcohol Use Disorder

Chronic alcohol and other psychoactive substance use is accompanied not only by disturbances in classical neurotransmitter systems but also by persistent activation of innate and adaptive immunity, leading to neuroinflammation. This review summarizes experimental and clinical data on how microglia and astrocytes act as central mediators at the intersection of immune, metabolic, and neuronal processes in alcohol-related disorders. We discuss Toll-like receptor 4 (TLR4)-dependent pathways, activation of the NLRP3 inflammasome, impaired glutamate clearance, metabolic "reprogramming" of glia, and mitochondrial dysfunction. These changes lead to energy deficiency, oxidative stress, and persistent remodeling of reward, stress, and cognitive control networks. Particular attention is given to the impact of neuroinflammation on dopaminergic, glutamatergic, GABAergic, and serotonergic neurotransmission, including the shift of tryptophan metabolism toward the kynurenine pathway. We also consider the role of the gut-liver-brain axis, dysbiosis, endotoxemia, systemic inflammation, and impaired production of short-chain fatty acids in maintaining neuroimmune-metabolic stress. Contribution of hepatic and adipose tissue to the formation of a chronic inflammatory milieu and its effect on blood-brain barrier (BBB) permeability is discussed. Based on the combined data, the authors propose an integrative model of dependence as a state arising at the intersection of disrupted neural signaling, disordered energy metabolism, and altered inter-organ communication. Promising therapeutic targets are outlined, including normalization of glial function, modulation of the gut microbiota, reduction of systemic inflammation, and targeting energy metabolism. The need to develop biomarker panels to identify subgroups of patients with the pronounced neuroinflammatory burden is emphasized.