Dual role of nicotine in addiction and cognition: a review of neuroimaging studies in humans

Abstract

Substantial evidence demonstrates both nicotine's addiction liability and its cognition-enhancing effects. However, the neurobiological mechanisms underlying nicotine's impact on brain function and behavior remain incompletely understood. Elucidation of these mechanisms is of high clinical importance and may lead to improved therapeutics for smoking cessation as well as for a number of cognitive disorders such as schizophrenia. Neuroimaging techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI), which make it possible to study the actions of nicotine in the human brain in vivo, play an increasingly important role in identifying these dual mechanisms of action. In this review, we summarize the current state of knowledge and discuss outstanding questions and future directions in human neuroimaging research on nicotine and tobacco. This research spans from receptor-level PET and SPECT studies demonstrating nicotine occupancy at nicotinic acetylcholine receptors (nAChRs) and upregulation of nAChRs induced by chronic smoking; through nicotine's interactions with the mesocorticolimbic dopamine system believed to mediate nicotine's reinforcing effects leading to dependence; to functional activity and connectivity fMRI studies documenting nicotine's complex behavioral and cognitive effects manifest by its actions on large-scale brain networks engaged both during task performance and at rest. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'.

Keywords: Addiction; Cognition; Dopamine; Nicotine; PET; SPECT; Smoking; Tobacco; fMRI.

Published by Elsevier Ltd.

Figures

Figure 1

Positron emission tomography (PET) studies using 2-[18F]fluoro-3-(2(S)- azetidinylmethoxy) pyridine (abbreviated as 2-FA) to image α4β2* nicotinic acetylcholine receptor (nAChR) occupancy from cigarette smoke exposure in humans in vivo. (A) Nicotine intake obtained from cigarette smoking in amounts used by typical daily smokers leads to nearly complete occupancy of α4β2* nAChRs, indicating that tobacco-dependent smokers maintain α4β2* nAChR saturation throughout the day. Horizontal slices at the level of the thalamus are shown. Modified from (Brody et al., 2006a). (B) Relatively small amounts of nicotine in a denicotinized cigarette (Q-3, 0.05 mg nicotine) and a low-nicotine cigarette (Q-1, 0.6 mg nicotine) result in 26% and 79% α4β2* nAChR occupancies, respectively, across thalamus (top panel), brainstem (bottom panel), and cerebellum (not shown). Modified from (Brody et al., 2009b). (C) Similarly, nicotine from moderate second-hand smoke exposure results in 19% occupancy of α4β2* nAChRs in both smokers (shown) and non-smokers. Modified from (Brody et al., 2011).

Figure 2

Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) and regional cerebral blood flow (rCBF) PET studies of nicotine effects on functional brain networks during (A–B) task-free resting state and (C–D) cognitive task performance. (A) Activation in the executive control network (ECN), encompassing ACC, DLPFC, and PPC, is anti-correlated with the default mode network (DMN), containing MPFC and PCC, during task-free resting state (top panel). Relative to placebo, nicotine enhanced the ECN-DMN anti-correlation in abstinent smokers who demonstrated a reduction in withdrawal symptoms following nicotine replacement (top time-course), but not in those who did not show such response (bottom time-course). Modified from (Cole et al., 2010). (B) Nicotine decreased DMN activity (including MPFC and PCC) relative to pre-nicotine baseline during resting state in non-smokers. Modified from (Tanabe et al., 2011). (C) Nicotine enhanced deactivation in the DMN (including MPFC and PCC) during a spatial attention task in minimally deprived smokers relative to placebo. Modified from (Hahn et al., 2007). (D) Using rCBF PET, nicotine enhanced DLPFC response (within the ECN) during 2-back working memory task in ex-smokers but reduced it in ex-smokers, relative to placebo. Modified from (Ernst et al., 2001). Abbreviations: ACC, anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex; DMN, default mode network; ECN, executive control network; MPFC, medial prefrontal cortex; PCC, posterior cingulate cortex; PPC, posterior parietal cortex.

Figure 3

A simplified diagram of nicotine’s dual action in the brain. Nicotine’s reinforcing and cognition-enhancing properties may be linked at least in part by nicotine-induced enhancement of DA signaling in the mesolimbic and mesocortical DA pathways, respectively. ACC, anterior cingulate cortex; DARs, dopamine receptors; NAc, nucleus accumbens; nAChRs, nicotinic acetylcholine receptors; PFC, prefrontal cortex; VST, ventral striatum; VTA, ventral tegmental area.