Lack of effect of 5HT 3 antagonist in mediating subjective and behavioral responses to cotinine Dorothy K. Hatsukami a, * , Joni Jensen a , Lisa H. Brauer a , Marc Mooney a , Susan Schulte b , Mehmet Sofuoglu c , Paul R. Pentel d a Tobacco Use Research Center, University of Minnesota, 2701 University Avenue, #201, Minneapolis, MN 55414, USA b Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA c Department of Psychiatry, Yale University, New Haven, CT 06519, USA d Department of Medicine, Hennepin County Medical Center and University of Minnesota, Minneapolis, MN 55415, USA Received 22 July 2002; received in revised form 3 January 2003; accepted 22 January 2003 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. D 2003 Published by Elsevier Science Inc. Keywords: Nicotine withdrawal; 5HT 3 antagonists; Nicotine patch; cotinine 1. Introduction Recent human studies have suggested that cotinine, a metabolite of nicotine, may have effects opposite of nicotine or antagonize the effects of nicotine. In one study, oral cotinine fumarate in doses up to 200 mg dose-dependently increased ratings of restlessness and impatience among abstinent smokers (Schuh et al., 1996). In another study using a 2  2 placebo-controlled design with one factor associated with placebo vs. 80 mg of cotinine fumarate and the other factor nicotine vs. placebo patch, 80 mg of cotinine blocked the effects of the nicotine patch in reducing withdrawal symptoms (Hatsukami et al., 1998b). In a third study, administration of a high dose of cotinine fumarate (160 mg) increased serum nicotine blood levels compared to placebo or a low dose of cotinine during ad lib smoking, suggesting the occurrence of compensatory smoking result- ing from antagonist activity (Hatsukami et al., 1998a). Moreover, studies conducted in laboratory animals have shown that cotinine blocks some of the physiological and hormonal biosynthesis responses from nicotine (Chahine et al., 1996, 1990; Kim et al., 1968). High levels of cotinine are necessary to achieve antagon- ist or effects opposite of nicotine. For example, the cotinine levels attained during the nicotine patch and 80 mg cotinine study were three to four times higher than that attained during ad lib smoking. Similarly, the levels of cotinine attained to observe antagonist effects on smoking behavior were around nine times higher than observed during ad lib smoking. Nonetheless, further study is warranted even though the venous levels of cotinine observed in these studies are greater than levels observed during ad lib smoking. Brain levels of cotinine achieved during smoking 0091-3057/03/$ – see front matter D 2003 Published by Elsevier Science Inc. doi:10.1016/S0091-3057(03)00035-2 * Corresponding author. Tel.: +1-612-626-5168; fax: +1-612-627- 4899. E-mail address: hatsu001@umn.edu (D.K. Hatsukami). www.elsevier.com/locate/pharmbiochembeh Pharmacology, Biochemistry and Behavior 75 (2003) 1 –7