Neural basis of smoking-induced relief of craving and negative affect: Contribution of nicotine.

Paul Faulkner,Neil E Paterson,Chelsea Cox,Edythe D London,Dara G Ghahremani,Gerhard Hellemann,Rachel F Tyndale,Nathaniel Ginder

doi:10.1111/adb.12679

Abstract

Smoking-induced relief of craving and withdrawal promotes continued cigarette use. Understanding how relief is produced and the role of nicotine in this process may facilitate development of new smoking-cessation therapies. As the US Food and Drug Administration considers setting a standard for reduced nicotine content in cigarettes to improve public health, knowledge of how nicotine contributes to relief also can inform policy. We assessed effects of nicotine using resting state functional magnetic resonance imaging (MRI) and behavioral assessments of craving and negative affect. Twenty-one young (18-25years old) daily smokers underwent overnight abstinence on 4days. On each of the following mornings, they self-rated their cigarette craving and negative affect and underwent resting-state functional MRI (fMRI) before and after smoking a cigarette that delivered 0.027, 0.110, 0.231, or 0.763mg of nicotine. Functional connectivity between the anterior insula and anterior cingulate cortex (ACC) and between the nucleus accumbens and orbitofrontal cortex (OFC) was assessed. Smoking reduced craving, negative affect, and nucleus accumbens-OFC connectivity irrespective of nicotine dose, with positive correlations of the effects on behavioral and connectivity measures. Only the highest nicotine dose (0.763mg) reduced right anterior insula-ACC connectivity; this reduction was positively correlated with the behavioral effects of the 0.763-mg dose only. While nicotine-based therapies may act on right anterior insula-ACC functional circuits to facilitate smoking cessation, non-nicotine (eg, the conditioned and sensorimotor) aspects of smoking may promote cessation by reducing OFC-accumbens connectivity to alleviate withdrawal.

Highlights

As a leading contributor to preventable disease and death worldwide, smoking causes an estimated 540,000 deaths per year in the U.S alone (Carter et al, 2015)
As the US Food and Drug Administration considers setting a standard for reduced nicotine content in cigarettes to improve public health, knowledge of how nicotine contributes to relief can inform policy
We recently showed that fast metabolizers of nicotine report nicotine dose-dependent reductions in cigarette craving but slow metabolizers do not (Faulkner et al, 2017); we included the nicotine metabolite ratio (NMR) as a separate factor to control for this variable

Summary

Introduction

As a leading contributor to preventable disease and death worldwide, smoking causes an estimated 540,000 deaths per year in the U.S alone (Carter et al, 2015). In this study of the neural mechanisms of smoking-induced relief of craving and negative affect during abstinence, one objective was to identify the contribution of nicotine per se. Another goal was to provide empirical data regarding potential acute effects of reducing nicotine content in cigarettes, as the US Food and Drug Administration is considering policy to set a maximum level of nicotine content in cigarettes to render them minimally addictive (Gottlieb and Zeller, 2017). A simulation model with inputs derived from empirical evidence has predicted that reducing the nicotine yield of cigarettes to 0.4 mg would reduce the number of smokers in the U.S by ~13 million within five years (Apelberg et al, 2018)

Methods

Results

Conclusion