title: Lack of effect of 5HT3 antagonist in mediating subjective and behavioral responses to cotinine.
abstract: Previous studies have shown that cotinine, a metabolite of nicotine, may antagonize some of the therapeutic effects of nicotine. The mechanisms underlying cotinine's effects are unclear, but cotinine has been observed to increase serotonin levels in the brain. Thus, it is possible that blocking serotonin effects may antagonize the actions of cotinine, thereby reducing its impact on responses to nicotine. This study determined whether granisetron, a 5HT(3) receptor antagonist, would enhance the efficacy of the nicotine patch. Subjects were randomly assigned to one of the three granisetron conditions (N=43 for 2 mg/day; N=43 for 1 mg/day; N=42 for 0 mg/day) and asked to take the assigned medication daily during 15 days of tobacco abstinence. Because we were interested in interactions between cotinine and serotonin, all groups were also treated with a 21-mg nicotine patch. Assessments of withdrawal symptoms were made for 1 week during baseline smoking and several times during the experimental period. There was a near but nonsignificant difference among groups on a measure of tobacco withdrawal and no significant differences on global measures of drug effects or physiological measures. The data do not strongly support the hypothesis that 5HT(3) agonism is the mechanism by which cotinine offsets the effects of nicotine.
authors.affiliation: Tobacco Use Research Center, University of Minnesota, 2701 University Avenue, #201, Minneapolis, MN 55414, USA. hatsu001@umn.edu
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Hatsukami
authors.forename: Joni
authors.initials: J
authors.lastname: Jensen
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Brauer
authors.forename: Marc
authors.initials: M
authors.lastname: Mooney
authors.forename: Susan
authors.initials: S
authors.lastname: Schulte
authors.forename: Mehmet
authors.initials: M
authors.lastname: Sofuoglu
authors.forename: Paul R
authors.initials: PR
authors.lastname: Pentel
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D001519:Behavior / Q000187:drug effects*; D003367:Cotinine / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D017829:Granisetron / Q000493:pharmacokinetics / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology; D010349:Patient Compliance; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D012907:Smoking / Q000523:psychology; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control / Q000523:psychology; D011795:Surveys and Questionnaires; D020340:Tobacco Use Cessation; D016896:Treatment Outcome
chemical_list: D003367:Cotinine; D017829:Granisetron; D009538:Nicotine; D018722:Nicotinic Agonists; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists