Potential roles of 5-HT3 receptor (5-HT3R) antagonists in modulating the effects of nicotine

Muhammad Harith Zulkifli; Praveena Viswenaden; Malina Jasamai; Norazrina Azmi; Nor Syafinaz Yaakob

doi:10.1016/j.biopha.2019.108630

Potential roles of 5-HT₃ receptor (5-HT₃R) antagonists in modulating the effects of nicotine

Biomed Pharmacother. 2019 Apr:112:108630. doi: 10.1016/j.biopha.2019.108630. Epub 2019 Feb 21.

Authors

Muhammad Harith Zulkifli¹, Praveena Viswenaden¹, Malina Jasamai¹, Norazrina Azmi¹, Nor Syafinaz Yaakob²

Affiliations

¹ Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300, Kuala Lumpur, Malaysia.
² Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300, Kuala Lumpur, Malaysia. Electronic address: nsy@ukm.edu.my.

PMID: 30797147
DOI: 10.1016/j.biopha.2019.108630

Abstract

5-HT₃R antagonists such as ondansetron, granisetron and tropisetron have been clinically used to treat nausea and vomiting in chemotherapy patients. However, current study and research revealed novel potentials of these ligands in other diseases like inflammation, Alzheimer's, and drug abuse. Towards utilising these drugs as anti-smoking agents to treat nicotine dependence problem, there are conflicting reports regarding the potential of these ligands in modulating the effects of nicotine in both human and animal behavioural studies. This is complicated by the heterogeneity of 5-HT₃R itself, cross regulation between nicotinic acetylcholinergic receptor (nAChR) and distinct pharmacological profiles of 5-HT₃R antagonists. This review gathered existing studies conducted investigating the potential of "-setron" class of 5-HT₃R antagonists in modulating nicotine effects. We proposed that the mechanism where 5-HT₃R antagonists mediate the effects of nicotine could be attributed by both direct at 5-HT₃R and indirect mechanism in nicotine addiction downstream regulation. The indirect mechanism mediated by the 5-HT₃R antagonist could be through α7 nAChR, 5-HT_1B receptor (5-HT_1BR), 5-HT_1C receptor (5-HT_1CR), calcineurin activity, p38 MAPK level, PPAR-γ and NF-κβ. Our review suggested that future studies should focus on newer 5-HT₃R antagonist with superior pharmacological profile or the one with multitarget action rather than high selectivity at single receptor.

Keywords: 5-HT(3) receptor; Addiction; Nicotine; Serotonin; Smoking.

Publication types

Review

MeSH terms

Humans
Palonosetron / pharmacology*
Palonosetron / therapeutic use
Receptors, Serotonin, 5-HT3 / genetics
Receptors, Serotonin, 5-HT3 / metabolism*
Serotonin 5-HT3 Receptor Antagonists / pharmacology*
Serotonin 5-HT3 Receptor Antagonists / therapeutic use
Tobacco Use Disorder / drug therapy*
Tobacco Use Disorder / genetics
Tobacco Use Disorder / metabolism

Substances

Receptors, Serotonin, 5-HT3
Serotonin 5-HT3 Receptor Antagonists
Palonosetron