We analyzed time to relapse to smoking in the subset of subjects who successfully quit smoking while on treatment during weeks 9–12, but relapsed during weeks 13–52. Unexpectedly, the strongest associations with this phenotype were with polymorphisms in genes encoding the serotonin receptors HTR3A and HTR3B. These genes were originally included in our study to test whether they might be related to nausea associated with varenicline treatment, although they are expressed widely in the brain as well as the gut (Niesler et al, 2008). Previous investigations using an HTR3 antagonist, ondansetron, provide some insights into why these loci may be important for relapse to smoking. This medicine, originally developed to prevent nausea (Cubeddu et al, 1990), has been shown to lower cravings for alcohol and to ease the withdrawal symptoms of opioid addictions (Chu et al, 2009; Johnson et al, 2002). These results and our observations raise the intriguing possibility that this serotonin receptor family may be mediating its effects on relapse by impacting nicotine withdrawal symptoms, suggesting a potential role for HTR3 inhibition in reducing such withdrawal symptoms, regardless of the initial treatment method.
