Enhanced dopamine release by nicotinein cigarette smokers: a double-blind,randomized, placebo-controlled pilot studyHidehiko Takahashi1, Yota Fujimura1, Mika Hayashi2, Harumasa Takano1,Motoichiro Kato2, Yoshiro Okubo3, Iwao Kanno1, Hiroshi Ito1and Tetsuya Suhara11Molecular Imaging Centre, Department of Molecular Neuroimaging, National Institute of Radiological Sciences, Anagawa,Inage-ku, Chiba, Japan2Department of Neuropsychiatry, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan3Department of Neuropsychiatry, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, JapanAbstractPrevious studies of smoking on dopamine release in humans were investigated only in smokers. Usingnicotine gum, we examined the effect of nicotine on dopamine release in smokers and non-smokers and itsrelation to the degree of nicotine dependence. Smokers and non-smokers participated in a double-blind,randomized, placebo-controlled cross-over study. They participated in two PET measurements with[11C]raclopride, in which they received either nicotine or placebo. Changes in [11C]raclopride non-displaceable binding potential (BPND) following nicotine administration were quantified. Smokersshowed significant decrease in BP in the striatum following nicotine administration, but non-smokers didnot show such a decrease. The BPNDdifference between the two scanning sessions was correlated with thedegree of nicotine dependence. The BPNDdifference might reflect enhanced dopamine release in smokersand the reinforced effect of nicotine. These data suggest the feasibility of our gum method as well as theimportance of the degree of dependence in future studies of the nicotine effect on the dopamine system.Received 15 May 2007; Reviewed 4 July 2007; Revised 18 August 2007; Accepted 25 August 2007;First published online 22 October 2007Key words: Dependence, dopamine, nicotine, positron emission tomography, striatum.IntroductionNicotine is a major psychostimulant component oftobacco. Repeated nicotine exposure can inducenicotine dependence (Laviolette and van der Kooy,2004; Olausson et al., 2003). It has been suggestedthat the mesolimbic dopamine pathway is involvedin nicotine dependence (Yasuno et al., 2007). [11C]raclo-pride has been used for the indirect measurement ofchanges in synaptic dopamine concentration in vivousing PET in response to addictive drugs like cocaineand amphetamine (Dewey et al., 1993). Dopamineis thought to compete with [11C]raclopride at the D2receptor, and dopamine release is associated witha reduction in [11C]raclopride binding (Dewey et al.,1993). Decreases in [11C]raclopride binding potential(BP) in the ventral striatum have been demonstratedin smokers following cigarette smoking (Brody et al.,2004, 2006; Scott et al., 2007). On the other hand, twohuman PET studies of smokers (Barrett et al., 2004;Montgomery et al., 2007) and an awake-monkey study(Tsukada et al., 2002) showed no overall changesin [11C]raclopride BP after exposure to nicotine.However, the monkeys were nicotine-naive, and thestudy by Montgomery et al. mainly examined low-dependence smokers. It can be expected that thedegree of nicotine dependence affects dopaminerelease in the brain (Scott et al., 2007). In this study, weused nicotine gum with the aim of exposing non-smokers to nicotine to the same degree as smokers.Another objective of this pilot study was to examinethe feasibility of nicotine gum methods. The study wasconducted in a double-blind, randomized, placebo-controlled manner.Address for correspondence: T. Suhara, M.D., Ph.D., MolecularImaging Centre, Department of Molecular Neuroimaging, NationalInstitute of Radiological Sciences, 9-1, 4-chome, Anagawa, Inage-ku,Chiba, Chiba 263-8555, Japan.Tel.: +81-43-206-3194 Fax: +81-43-253-0396E-mail: [email protected] Journal of Neuropsychopharmacology (2008), 11, 413–417. Copyright f 2007 CINPdoi:10.1017/S1461145707008103BRIEF REPORTCINPMethodParticipantsTwelve male subjects (six smokers, mean age 25.8¡2.6 yr, and six non-smokers, 23.7¡2.7 yr) participatedin a double-blind, randomized, placebo-controlled,cross-over pilot study. Smokers had a smoking historyof at least 4 yr, with current use of o15 cigarettes perday. The Fagerstrom test for nicotine dependence(FTND) was applied (Heatherton et al., 1991). TheFTND, consisting of six questions (e.g. How soonafter you wake up do you smoke your first cigarette?How many cigarettes per day do you smoke?), yieldsa score ranging from 0 to 10 (0–2, very low depen-dence; 8–10 very high dependence). The non-smokershad no history of recreational use of cigarettes. Noneof the subjects were taking alcohol at the time, nor didthey have a history of psychiatric disorder, significantphysical illness, head injury, neurological disorder, oralcohol or drug (other than nicotine) dependence. MRIdemonstrated intact cerebral structures in all subjects.All subjects were right-handed according to theEdinburgh Handedness Inventory. Smokers were in-structed not to smoke for 24 h before scanning, andabstinence was verified by plasma nicotine measure-ment. Both before and after the administration ofnicotine, the strength of cigarette craving was assessedusing a 6-point scale (0=no urge, 5=extremely strongurge). After description of the study to the subjects,written informed consent was obtained, and the studywas approved by the Ethics and Radiation SafetyCommittee of the National Institute of RadiologicalSciences, Japan.Nicotine administrationEach subject participated in two PET sessions. Toensure maximum and stable plasma concentrations ofnicotine during the PET scans, 1 h before each scan thesubjects received two pieces of either nicotine (2 mgNicorette, mint taste ; Pfizer, Tokyo, Japan) or taste-matched placebo gum. A clinical research coordinator(Y.F.), generated the randomization sequence (theorder of the two sessions) and packaged the placeboand nicotine gum in containers according to thebalanced randomization list (half of the subjects tooknicotine gum first, and the remaining half took placebogum first). The participants and all study staff and in-vestigators, except Y.F., remained blinded to the treat-ment allocation throughout the study. Every 3 min, thesubjects chewed the gum five times at a rate of 1 Hzand then put the gum into the oral vestibule in front ofthe lower anterior teeth. Until the start of the PETscans, the subjects were trained to chew the gum whilenot moving the maxilla but