Despite improvements in tobacco control, the prevalence of cigarette smoking remains high at 27% among Veterans and 21% among the general U.S. population (~46 million U.S. adults). Of these smokers, approximately 33% smoke menthols, meaning that roughly 9% of all Veterans smoke menthol cigarettes. In addition to menthol cigarette usage being prevalent among Veterans, this problem is likely to worsen over time, because recent military deployments increase the chances of smoking initiation and marketing of menthol cigarettes is aimed at roughly the age group that comprises the active military. A central difficulty with menthol cigarettes is that smokers who use them have lower cessation rates in standardized treatment programs than smokers who use non-menthol cigarettes. Though many factors have been implicated in the initiation and continued usage of menthol cigarettes, studies of biological markers of smoking demonstrate that menthol itself inhibits nicotine metabolism, and that menthol cigarette smoking leads to elevated serum levels of nicotine and cotinine, and greater exhaled carbon monoxide levels. These elevated levels would be expected to up-regulate the density of brain 1422* nicotinic acetylcholine receptors (nAChRs), which could mediate the greater severity of Tobacco Dependence found in menthol cigarette smokers;however, these points have not yet been demonstrated in human smokers. Based on prior literature and pilot data collected for this grant application, the primary hypothesis for the proposed research are that: 1) pre-treatment 1422* nAChR densities in the thalami (and other brain regions of interest) will be higher in menthol than non-menthol cigarette smokers, 2) menthol cigarette smokers will have greater reductions in 1422* nAChR density in the thalami (and other brain regions of interest) from before to after quitting smoking (with combination treatment with the nicotine patch, cognitive behavioral group psychotherapy, and contingency management) than non-menthol cigarette smokers, 3) menthol cigarette smokers who quit smoking with treatment (compared to those who receive treatment but do not quit) will have greater reductions in 1422* nAChR density in the regions of interest than non-menthol cigarette smokers who quit (compared to those who do not quit), and 4) lesser severity of 1422* nAChR up-regulation at baseline (along with clinical factors such as lesser severity of nicotine dependence) will be associated with better treatment outcomes, including an improved likelihood of quitting and/or decreasing smoking. To test these hypotheses, menthol and non-menthol cigarette smokers will be recruited through flyers distributed at the VA Greater Los Angeles Smoking Cessation Programs. Participants will undergo the following sequence of procedures: (1) telephone/in-person screening, (2) a bolus-plus-continuous-infusion 2- FA positron emission tomography (PET) scanning session, (3) a structural magnetic resonance imaging scan within one week of the initial PET session, (4) ten weeks of standard treatment with a nicotine patch taper plus cognitive-behavioral group psychotherapy (CBT), (5) four weeks of treatment with continued CBT plus contingency management (CM), and (6) a follow-up 2-FA PET session with the same protocol as the initial PET session at the end of the 14-week treatment period. Rating scales for the determination of smoking- related symptoms will be collected before, during, and at the end of treatment. Smoking status and measures of nicotine exposure and metabolism will be collected throughout the study using participant reports, exhaled carbon monoxide (CO) levels, urine cotinine levels, and plasma nicotine, cotinine, and 3'-hydroxycotinine levels. PET data will be analyzed to determine the total volume of distribution (VT) in primary brain regions of interest (a measure directly proportional to 4 2* nAChR density). For the central study analyses, differences in pre-treatment VT levels between menthol and non-menthol smokers will be determined, followed by a comparison of changes in VT levels between menthol and non-menthol smokers who quit with treatment. A comparison of VT level change in menthol and non-menthol smokers will also be performed including quit status as a factor. And, the predictive value of pre-treatment VT levels (and other smoking-related variables) in determining who will quit with treatment will also be determined. If the central hypotheses hold true, this study will identify a potential mediating factor for the relative severity of addiction to menthol cigarettes, which results in these smokers having more difficulty quitting than non-menthol cigarette smokers. Thus, the proposed study may contribute to our understanding of the relationships between brain 1422* nAChR densities, menthol cigarette smoking, subjective symptoms of Nicotine Dependence, nicotine metabolism, and treatment outcomes, and may (in the future) have implications for the treatment of menthol cigarette smokers.

Public Health Relevance

Cigarette smoking is more prevalent among Veterans (27%) than the general U.S. population (21%), with the use of menthol cigarettes becoming increasingly common, affecting approximately 9% of the Veteran population. In addition to being common, the problem of menthol cigarette usage among Veterans is likely to increase over time, because military deployment increases the chances of smoking initiation and because marketing of menthol cigarettes is currently aimed at roughly the age group that comprises the active military. A central difficulty with menthol cigarettes is that smokers who use them have lower cessation rates in standardized treatment programs than smokers who use non-menthol cigarettes. For the proposed study, brain imaging will be used to determine 1422* nicotinic acetylcholine receptor (nAChR) densities in menthol and non-menthol Veteran cigarette smokers, along with the effects of quitting smoking on these receptor densities. Results of the proposed research may have implications for improving treatments for menthol (and non- menthol) cigarette smoking Veterans.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology A (NURA)
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VA Greater Los Angels Healthcare System
Los Angeles
United States
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