5-HT₃ Receptor Antagonists in Neurologic and Neuropsychiatric Disorders: The Iceberg Still Lies beneath the Surface

Abstract

HT 3 receptor antagonists, first introduced to the market in the mid-1980s, are proven efficient agents to counteract chemotherapy-induced emesis. Nonetheless, recent investigations have shed light on unappreciated dimensions of this class of compounds in conditions with an immunoinflammatory component as well as in neurologic and psychiatric disorders. The promising findings from multiple studies have unveiled several beneficial effects of these compounds in multiple sclerosis, stroke, Alzheimer disease, and Parkinson disease. Reports continue to uncover important roles for 5-HT 3 receptors in the physiopathology of neuropsychiatric disorders, including depression, anxiety, drug abuse, and schizophrenia. This review addresses the potential of 5-HT 3 receptor antagonists in neurology-and neuropsychiatry-related disorders. The broad therapeutic window and high compliance observed with these agents position them as suitable prototypes for the development of novel pharmacotherapeutics with higher efficacy and fewer adverse effects.

The Microbiota-Gut-Brain Axis: From Motility to Mood

“…162,163 Although serotonin can activate more than 15 receptors/ receptor subtypes in the brain and intestine, the majority of IBS research has focused on the 5-HT 3 and 5-HT 4 receptors because both have been shown to have effects on mood, motility, and abdominal pain. 113,[164][165][166][167] Altogether, these data suggest a possible role of the gut microbiome in altered brain-gut interactions in IBS. They also provide the basis for larger, longitudinal interventional studies, both clinical and functional, to identify the roles of specific microbiota in behavioral and gut dysfunction in IBS and also the utility of serotonin-based modulators as potential therapeutic targets (Figure 2).…”

Asymmetric opening of the homopentameric 5-HT3A serotonin receptor in lipid bilayers

“…Here, we employ single-particle cryo-electron microscopy (cryo-EM) in combination with MD simulations to elucidate the gating mechanism of the homopentameric 5HT 3 R and its modulation by lipids. Besides being a therapeutic target 14 , the 5HT 3 R represents an interesting case as despite several structures having been reported for the receptor in detergent in the presence and absence of agonist [15][16][17][18] , the mechanism of gating remains an open question 19 . This is in part due to difficulties in unambiguously assigning functional states to static structures and the notable differences observed between the structures of the serotonin-bound receptor in detergent micelles 17,18 .…”

Opportunities for multiscale computational modelling of serotonergic drug effects in Alzheimer's disease

“…5-HT 3 , the only 5-HT based ligand-gated ion channel, acts via changes in cation currents (e.g., Na + , Ca 2+ ) ( Masson et al, 2012 ). Numerous studies have associated 5-HT 3 mediated drugs with the accumulation of specific proteins found in AD ( Fakhfouri et al, 2019 ; Huang et al, 2020 ; Skovgård et al, 2018 ). For example, in a rat model of AD, a study showed a protective response of a drug, tropisetron, a 5-HT 3 receptor antagonist, on Aβ-induced neurotoxicity on neurons in the hippocampus, a brain region associated with cognitive functions such as memory and spatial navigation ( Rahimian et al, 2013 ).…”