Potential roles of 5-HT receptor (5-HTR) antagonists in modulating the effects of nicotine.

5-HTR 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-HTR itself, cross regulation between nicotinic acetylcholinergic receptor (nAChR) and distinct pharmacological profiles of 5-HTR antagonists. This review gathered existing studies conducted investigating the potential of "-setron" class of 5-HTR antagonists in modulating nicotine effects. We proposed that the mechanism where 5-HTR antagonists mediate the effects of nicotine could be attributed by both direct at 5-HTR and indirect mechanism in nicotine addiction downstream regulation. The indirect mechanism mediated by the 5-HTR antagonist could be through α7 nAChR, 5-HT receptor (5-HTR), 5-HT receptor (5-HTR), calcineurin activity, p38 MAPK level, PPAR-γ and NF-κβ. Our review suggested that future studies should focus on newer 5-HTR antagonist with superior pharmacological profile or the one with multitarget action rather than high selectivity at single receptor.