Decoding the serotonin-alcohol crosstalk: the role of central serotonergic dysregulation in alcohol use disorder

Serotonin (5-hydroxytryptamine; 5-HT) is a key neuromodulator involved in the regulation of mood, appetite, aggression, and impulse control. Dysregulation of central 5-HT function has been implicated in alcohol use disorder (AUD) and comorbid depression. This review summarizes clinical and preclinical evidence on the role of 5-HT in AUD development, heterogeneity, and treatment response. Alterations in 5-HT function may be shaped by stress and genetic variation in serotonergic genes, including TPH2 and SLC6A4, contributing to individual vulnerability to AUD. Reduced 5-HT activity increases the risk of developing AUD, particularly Cloninger's type II, characterized by early onset, violent, and antisocial behaviors. Consistently, Tph2-deficient mice, which lack central 5-HT, exhibit increased ethanol consumption and behavioral features resembling Cloninger's type II alcohol dependence. Similarly, alcohol-preferring rat lines show reduced 5-HT levels, decreased serotonergic projections to the cortex, and reduced prefrontal 5-HT_2A receptor binding, implicating raphe-prefrontal serotonergic projections as a critical pathway modulating vulnerability to AUD. Given the heterogeneity of AUD, the efficacy of selective 5-HT reuptake inhibitors (SSRIs) remains limited, with beneficial effects observed only in less severe, later-onset forms. Recently, serotonergic psychedelic-assisted therapies have attracted considerable interest as potential AUD treatments; mechanistically, their effects may be linked to activation of 5-HT_2A receptors in the prefrontal cortex - a brain region known to be dysfunctional in AUD. The reviewed literature highlights the need for improved stratification of AUD subtypes and validation of 5-HT-related biomarkers to guide personalized therapeutic approaches.