Brain nicotinic acetylcholine receptor availability and response to smoking cessation treatment: a randomized trial

Abstract

Importance: Cigarette smoking leads to upregulation of nicotinic acetylcholine receptors (nAChRs) in the human brain, including the common α4β2* nAChR subtype. While subjective aspects of tobacco dependence have been extensively examined as predictors of quitting smoking with treatment, no studies to our knowledge have yet reported the relationship between the extent of pretreatment upregulation of nAChRs and smoking cessation.

Objective: To determine whether the degree of nAChR upregulation in smokers predicts quitting with a standard course of treatment.

Design, setting, and participants: Eighty-one tobacco-dependent cigarette smokers (volunteer sample) underwent positron emission tomographic (PET) scanning of the brain with the radiotracer 2-FA followed by 10 weeks of double-blind, placebo-controlled treatment with nicotine patch (random assignment). Pretreatment specific binding volume of distribution (VS/fP) on PET images (a value that is proportional to α4β2* nAChR availability) was determined for 8 brain regions of interest, and participant-reported ratings of nicotine dependence, craving, and self-efficacy were collected. Relationships between these pretreatment measures, treatment type, and outcome were then determined. The study took place at academic PET and clinical research centers.

Main outcomes and measures: Posttreatment quit status after treatment, defined as a participant report of 7 or more days of continuous abstinence and an exhaled carbon monoxide level of 3 ppm or less.

Results: Smokers with lower pretreatment VS/fP values (a potential marker of less severe nAChR upregulation) across all brain regions studied were more likely to quit smoking (multivariate analysis of covariance, F8,69 = 4.5; P < .001), regardless of treatment group assignment. Furthermore, pretreatment average VS/fP values provided additional predictive power for likelihood of quitting beyond the self-report measures (stepwise binary logistic regression, likelihood ratio χ21 = 19.8; P < .001).

Conclusions and relevance: Smokers with less upregulation of available α4β2* nAChRs have a greater likelihood of quitting with treatment than smokers with more upregulation. In addition, the biological marker studied here provided additional predictive power beyond subjectively rated measures known to be associated with smoking cessation outcome. While the costly, time-consuming PET procedure used here is not likely to be used clinically, simpler methods for examining α4β2* nAChR upregulation could be tested and applied in the future to help determine which smokers need more intensive and/or lengthier treatment.

Trial registration: clinicaltrials.gov Identifier: NCT01526005.

Figure 1

Study Regions of Interest Shown on a Representative Magnetic Resonance Imaging Scan.

Figure 2

Mean Pretreatment Positron Emission Tomographic Images From the Study Subgroups Demonstrating Higher 2-FA Binding at Baseline in Nonquitters Compared With Quitters Mean pretreatment positron emission tomographic scans are shown for nonquitters and quitters treated with nicotine patch and for those treated with placebo patch. Positron emission tomographic images were spatially normalized to the group mean magnetic resonance imaging scan. V_S/f_P indicates specific binding volume of distribution.