Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers

Abstract

One-third of smokers primarily use menthol cigarettes and usage of these cigarettes leads to elevated serum nicotine levels and more difficulty quitting in standard treatment programmes. Previous brain imaging studies demonstrate that smoking (without regard to cigarette type) leads to up-regulation of β(2)*-containing nicotinic acetylcholine receptors (nAChRs). We sought to determine if menthol cigarette usage results in greater nAChR up-regulation than non-menthol cigarette usage. Altogether, 114 participants (22 menthol cigarette smokers, 41 non-menthol cigarette smokers and 51 non-smokers) underwent positron emission tomography scanning using the α(4)β(2)* nAChR radioligand 2-[(18)F]fluoro-A-85380 (2-FA). In comparing menthol to non-menthol cigarette smokers, an overall test of 2-FA total volume of distribution values revealed a significant between-group difference, resulting from menthol smokers having 9-28% higher α(4)β(2)* nAChR densities than non-menthol smokers across regions. In comparing the entire group of smokers to non-smokers, an overall test revealed a significant between-group difference, resulting from smokers having higher α(4)β(2)* nAChR levels in all regions studied (36-42%) other than thalamus (3%). Study results demonstrate that menthol smokers have greater up-regulation of nAChRs than non-menthol smokers. This difference is presumably related to higher nicotine exposure in menthol smokers, although other mechanisms for menthol influencing receptor density are possible. These results provide additional information about the severity of menthol cigarette use and may help explain why these smokers have more trouble quitting in standard treatment programmes.

Conflict of interest statement

Statement of Interest: Drs Brody and Mandelkern were previously co-investigators on a grant funded by Pfizer, Inc., which was unrelated to this study. Dr Mukhin is a co-investigator on a grant from Phillip Morris, Inc., for research unrelated to this study.

Figures

Fig. 1

Both non-menthol and menthol cigarette smokers have higher α4β2* nicotinic acetylcholine receptor (nAChR) densities than non-smokers in the brainstem, cerebellum, prefrontal cortex and corpus callosum. Levels of nAChRs for the non-menthol and menthol smoker groups are compared to the non-smoker group (100%) and to one another. For comparisons with the non-smoker group, * p<0.05, ** p<0.005 and *** p<0.0005 (uncorrected). For comparisons between the non-menthol and menthol smoker groups, ## p<0.01 (uncorrected). Statistics are generally the same for specific binding volume of distribution (Vs/fp) values in this figure as for the Vt/fp values in Table 2, because the same non-displaceable volume of distribution (VND) values are subtracted from each participant's Vt/fp values to obtain Vs/fp values.

Fig. 2

Menthol cigarette smokers have greater α4β2* nicotinic acetylcholine receptor (nAChR) up-regulation than non-menthol smokers. Averages of spatially normalized parametric images [specific binding volume of distribution (VS/fP)] obtained in the study from 51 non-smokers, 41 non-menthol cigarette smokers and 22 menthol cigarette smokers are shown. From left to right are transaxial, sagittal and coronal brain slices. The bottom row shows the mean T1-weighted magnetic resonance image (MRI) of study participants.