Greater nicotinic acetylcholine receptor density in smokers than in nonsmokers: a PET study with 2-18F-FA-85380

Abstract

Assays of human postmortem brain tissue have revealed that smokers have greater densities of high-affinity nicotinic acetylcholine receptors (nAChRs) in several brain regions than do nonsmokers or exsmokers. Quantitative PET imaging of nAChRs in humans has recently been reported using the alpha4beta2* subtype-specific radioligand 2-(18)F-FA-85380 (2FA).

Methods: We used PET and 2FA to measure total volumes of distribution corrected for the free fraction of 2FA in plasma (V(T)/f(P)) in 10 nonsmokers and 6 heavy smokers (>14 cigarettes/d; abstinent for >36 h). Dynamic PET scans were performed over 8 h, commencing immediately after a bolus injection of 2FA. Anatomic sampling was performed on PET images that were coregistered to MR images acquired from each volunteer. Data were analyzed by Logan plots and by 1- and 2-tissue-compartment models using unbound, unmetabolized arterial 2FA concentration as the input function.

Results: All modeling methods yielded similar results. V(T)/f(P) was significantly higher in smokers than in nonsmokers in all brain regions tested, except the thalamus. We used measures of V(T)/f(P) and estimates of nondisplaceable volume of distribution and found 25%-200% higher values in smokers than in nonsmokers for the volume of distribution for the specific binding compartment in the frontal cortex, midbrain, putamen, pons, cerebellum, and corpus callosum. These findings were consistent with voxel-based analysis using statistical parametric mapping.

Conclusion: Our findings suggest that PET with 2FA can be used to study the role of nicotine-induced upregulation of nAChRs in active smokers and during smoking cessation.

FIGURE 1

Time–activity curves for total radioactivity (triangles) and for radioactivity corresponding to unmetabolized 2FA (circles) in smokers (open symbols) and nonsmokers (filled symbols), presented as SUV (fraction of injected dose/g of body weight absorbed in 1 g of tissue). Insert shows same data with expanded y-axis. Values are given as mean ± SEM.

FIGURE 2

Time–activity curves showing radioactivity corresponding to unmetabolized 2FA as fraction of total radioactivity in smokers (○) and nonsmokers (●). Values are given as mean ± SEM.

FIGURE 3

Representative time–activity curves for several brain regions in a nonsmoker (A) and a smoker (B) for thalamus (Th), frontal cortex (frCx), cerebellum (Cb), midbrain (Midbr), pons, putamen (Put), and corpus callosum (Cc). As expected, peak radioactivity expressed as SUV for regions assayed was greatest for thalamus > putamen = pons > midbrain > cerebellum = frontal cortex > > corpus callosum for nonsmokers. SUV for smokers revealed similar pattern, but peak values were greater.

FIGURE 4

Values for V_T/f_P for various brain regions in nonsmokers (A) and smokers (B). Values were obtained by Logan graphical analysis and 1- and 2-tissue-compartment models (1TCM and 2TCM, respectively). Values are given as mean ± SD. CC = corpus callosum; FrCx = frontal cortex; Cb = cerebellum; Put = putamen; Midbr = midbrain; Th = thalamus.

FIGURE 5

Values for differences between smokers and nonsmokers in V_T/f_P for same brain regions shown in Figure 4 obtained by Logan graphical analysis and 1- and 2-tissue-compartment models (1TCM and 2TCM, respectively). Values are given as mean ± SD. CC = corpus callosum; FrCx = frontal cortex; Cb = cerebellum; Put = putamen; Midbr = midbrain; Th = thalamus.

FIGURE 6

SPM comparison of smokers and nonsmokers: average parametric map of nonsmokers (control), average parametric map of smokers, and SPM comparison of smokers and nonsmokers. All panels show areas of brain in which V_T/f_P was greater for smokers than for nonsmokers. Opposite comparison yielded no areas in which V_T/f_P was greater for nonsmokers than for smokers. Minimum number of contiguous voxels for this analysis was 100. For images shown, total number of voxels tested was 190,993, and 17,980 were significant using a corrected P value of 0.01.