Low 5HT_1B and 5HT₄ Receptor Neurotransmission as a Potential Link Between Cholesterol Metabolism and Suicide Risk

Elevated levels of the inflammatory cytokine IL-6 and decreased levels of cholesterol in blood and brain tissue have been reported in studies of individuals who attempted or completed suicide. The mechanisms underlying these effects remain unclear. In this review, we discuss a potential mechanistic link between these observations involving lipid raft function and serotonergic signaling. Reduced cholesterol availability may affect lipid raft function and could, potentially through reduced levels of the lipid raft protein S100A10 (p11), result in diminished cell-surface expression of the serotonin receptors 5-HT_1B and 5-HT₄. Both receptors have been implicated in the suppression of impulsive and aggressive behavior. Lipid rafts are also organizing platforms for GABA, glutamate, and serotonin transporters. Reduced serotonin reuptake could contribute to the often-reported decrease in the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in suicidal individuals. Inflammatory cytokines, including IL-6, may further influence serotonergic signaling by increasing expression of the enzyme indoleamine-2,3-dioxygenase (IDO), which enhances tryptophan degradation through the kynurenine pathway. Reduced tryptophan availability may limit serotonin synthesis and thereby decrease activation of the 5-HT_1B and 5-HT₄ receptors. These observations suggest that the combined effects of low cholesterol, elevated IL-6 signaling, and reduced tryptophan availability may increase impulsivity and thereby heighten vulnerability to suicidal behavior. This framework accommodates findings from genetic and biomarker studies in suicidal patients. Owing to its effect on lipid raft organization, the fish-oil component docosahexaenoic acid (DHA) might modulate these processes and potentially reduce suicide risk in individuals with low cholesterol levels.