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 β2*-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 α4β2* nAChR radioligand 2-[18F]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 α4β2* 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 α4β2* 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.

Cigarette smoking leads to upregulation of brain nicotinic acetylcholine receptors (nAChRs), including the common a 4 b 2 * nAChR subtype. Although a substantial percentage of smokers receive treatment for tobacco dependence with counseling and/or medication, the effect of a standard course of these treatments on nAChR upregulation has not yet been reported. In the present study, 48 otherwise healthy smokers underwent positron emission tomography (PET) scanning with the radiotracer 2-FA (for labeling a 4 b 2 * nAChRs) before and after treatment with either cognitive-behavioral therapy, bupropion HCl, or pill placebo. Specific binding volume of distribution (V S /f P ), a measure proportional to a 4 b 2 * nAChR density, was determined for regions known to have nAChR upregulation with smoking (prefrontal cortex, brainstem, and cerebellum). In the overall study sample, significant decreases in V S /f P were found for the prefrontal cortex, brainstem, and cerebellum of À 20 (±35), À 25 (±36), and À 25 (±31)%, respectively, which represented movement of V S /f P values toward values found in non-smokers (mean 58.2% normalization of receptor levels). Participants who quit smoking had significantly greater reductions in V S /f P across regions than non-quitters, and correlations were found between reductions in cigarettes per day and decreases in V S /f P for brainstem and cerebellum, but there was no between-group effect of treatment type. Thus, smoking reduction and cessation with commonly used treatments (and pill placebo) lead to decreased a 4 b 2 * nAChR densities across brain regions. Study findings could prove useful in the treatment of smokers by providing encouragement with the knowledge that decreased smoking leads to normalization of specific brain receptors.

Prior research indicates that disturbance of cholinergic neurotransmission reduces anxiety, leading to the hypothesis that people with heightened cholinergic function have a greater tendency toward anxiety-like and/or harm-avoidant behavior. We sought to determine if people with elevated levels of harm avoidance (HA), a dimension of temperament from the Temperament and Character Inventory (TCI), have high α4β2* nicotinic acetylcholine receptor (nAChR) availability. Healthy adults (n = 105; 47 non-smokers and 58 smokers) underwent bolus-plus-continuous infusion positron emission tomography (PET) scanning using the radiotracer 2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (abbreviated as 2-FA). During the uptake period of 2-FA, participants completed the TCI. The central study analysis revealed a significant association between total HA and mean nAChR availability, with higher total HA scores being linked with greater nAChR availability. In examining HA subscales, both ‘Fear of Uncertainty’ and ‘Fatigability’ were significant, based on higher levels of these characteristics being associated with greater nAChR availabilities. This study adds to a growing body of knowledge concerning the biological basis of personality and may prove useful in understanding the pathophysiology of psychiatric disorders (such as anxiety disorders) that have similar characteristics to HA. Study findings may indicate that heightened cholinergic neurotransmission is associated with increased anxiety-like traits.

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