Decoding the serotonin–alcohol crosstalk: the role of central serotonergic dysregulation in alcohol use disorder
Pharmacological Reports June 22, 2026 Magdalena Zaniewska
Serotonin (5-HT) is a key neuromodulator involved in mood, appetite, aggression, and impulse control. Dysregulation of central 5-HT function is implicated in alcohol use disorder (AUD) and comorbid depression. Reduced 5-HT activity increases the risk of developing AUD, particularly Cloninger's type II, characterized by early onset, violent, and antisocial behaviors. Tph2-deficient mice, which lack central 5-HT, exhibit increased ethanol consumption and behavioral features resembling type II alcohol dependence. Alcohol-preferring rat lines show reduced 5-HT levels, decreased serotonergic projections to the cortex, and reduced prefrontal 5-HT2A receptor binding. The efficacy of selective 5-HT reuptake inhibitors (SSRIs) is limited, with beneficial effects only in less severe, later-onset forms. Serotonergic psychedelic-assisted therapies may activate 5-HT2A receptors in the prefrontal cortex, a region dysfunctional in AUD.