Serotonin as a drug receptor for Li+: a computational study

Abstract

Although Li+ is widely used to treat bipolar disorder, its antidepressant pharmacological mechanism of action remains unelucidated. Herein, based on molecular modelling studies, we present the novel hypothesis that one possible receptor for Li+ is serotonin (5-hydroxytryptamine, 5-HT), a small molecule neurotransmitter rather than a large macromolecular protein. The resulting Li+/5-HT drug–receptor complex subsequently interacts with “upstream” macromolecular receptors such as the 5-HT1A receptor differently than 5-HT alone, producing an enhanced antidepressant effect. The notion that a neurotransmitter could itself be a receptor for a therapeutic is an interesting receptor cascade concept. Using molecular mechanics and semi-empirical and ab initio levels of theory, the potential interactions between Li+ and 5-HT and between Li+ and 5-HIAA (5-hydroxyindoleacetic acid, a 5-HT metabolite) were examined. Molecular dynamics simulations were then used to examine how Li+ affects the binding of 5-HT to its target 5-HT1A antidepressant receptor. The results of these calculations suggest that Li+ can interact with 5-HT and in such a way that it modifies the ligand–protein interactions.