Effects of Varenicline on Smoking Cue–Triggered Neural and Craving Responses

Abstract

Context Varenicline, an effective smoking cessation medication, functions as an α4β2 nicotinic acetylcholine receptor partial agonist. It indirectly affects the dopaminergic reward system by reducing withdrawal symptoms during abstinence and by decreasing the reinforcement received from nicotine while smoking. We hypothesize that varenicline would have a third mechanism to blunt responses to smoking cues in the reward-related ventral striatum and medial orbitofrontal cortex and would be associated with a reduction in smoking cue–elicited craving. Design A laboratory model of conditioned responding and arterial spin-labeled perfusion functional magnetic resonance imaging, a biomarker of regional brain activity, was used to test our hypothesis. Perfusion functional magnetic resonance imaging is quantitative and stable across time, facilitating the measurement of medication-induced neural modifications in the brain in response to a challenge (smoking cue exposure) and in the brain in the resting condition (without provocation). Smokers were imaged during rest and during smoking cue exposure before and after a 3-week randomized placebo-controlled medication regimen. Subjects were nonabstinent to explicitly examine the effects of varenicline on cue reactivity independent of withdrawal. Setting Center for the Study of Addictions, University of Pennsylvania, Philadelphia. Subjects Subjects were nicotine-dependent smokers who responded to advertisements placed on local radio and Listservs to participate in a medication-related research study that specifically stated “this is not a Quit Smoking Study” and “smokers may be contemplating but not currently considering quitting.” Results Prerandomization smoking cues vs nonsmoking cues activated the ventral striatum and medial orbitofrontal cortex (t=3.77) and elicited subjective reports of craving (P=.006). Craving reports correlated with increased activity in the posterior cingulate (t=4.11). Administration of varenicline diminished smoking cue– elicited ventral striatum and medial orbitofrontal cortex responses (t values from −3.75 to −5.63) and reduced self-reported smoking cue–elicited craving, whereas placebo-treated subjects exhibited responses similar to those observed prior to randomization. Varenicline-induced activation of lateral orbitofrontal cortex in the brain at rest (t=5.63) predicted blunting of smoking cue responses in the medial orbitofrontal cortex (r=−0.74). Conclusions Varenicline’s reciprocal actions in the reward-activated medial orbitofrontal cortex and in the reward-evaluating lateral orbitofrontal cortex underlie a diminished smoking cue response, revealing a distinctive new action that likely contributes to its clinical efficacy.

Reward Anticipation Is Differentially Modulated by Varenicline and Nicotine in Smokers

“…This informs the underlying neurobiological mechanisms of VAR's efficacy in smoking reduction. The observed downregulation of ACC is directionally consistent with VAR-mediated reductions in smoking-cue-related medial OFC activation in smokers (Franklin et al, 2011), as well as behavioral and subjective reports of reductions in nicotine craving in smokers administered VAR (Brandon et al, 2011;Patterson et al, 2009).…”

“…VAR has been broadly implicated in the reduction of reward signaling, selectively decreasing voluntary alcohol intake in both rodents (Hendrickson et al, 2010;Steensland et al, 2007) and humans (Fucito et al, 2011;McKee et al, 2009). Administration of VAR decreases subjective reports of nicotine craving (Brandon et al, 2011;Patterson et al, 2009) and smoking cue-induced activity in the medial OFC (Franklin et al, 2011) in nontreatmentseeking smokers. In addition, VAR reduces subjective reward of nicotine during lapses in smoking cessation (Oncken et al, 2006;Patterson et al, 2009).…”

A Single Administration of Low-Dose Varenicline Saturates α4β2* Nicotinic Acetylcholine Receptors in the Human Brain

“…In this study, given the saturation of a4b2* nAChRs by low-dose varenicline, its inability to reduce withdrawal symptoms after a single administration, confirms the importance of long-term administration to achieve withdrawal alleviation. Chronic effects of varenicline have recently been reported in the brain imaging literature, with findings demonstrating that as little as 3 weeks of treatment can reduce cue-associated brain reactivity in limbic reward regions in healthy non-abstinent smokers (Franklin et al, 2011). Thus, the findings suggest that visual 'cues' lead to brain activity (blood-oxygen-level dependence (BOLD) response) through an a4b2* nAChR mechanism, which can be blocked by varenicline.…”

“…Whether other sensory cues, such as smell, taste, and feel of a Low-dose varenicline saturates nicotinic receptors S Lotfipour et al cigarette, could work through similar mechanisms needs further exploration. Such effects may be driven by chronic varenicline-mediated modifications of the a4b2* nAChR densities in the brain (Franklin et al, 2011). Indeed, preclinical evidence demonstrates that chronic varenicline treatment can increase the density of a4b2* nAChRs after a 2-week administration (with behavioral correlates), similar to the effects of chronic nicotine exposure over the same time period (Turner et al, 2011).…”

Magnitude and duration of cue-induced craving for Marijuana in volunteers with cannabis use disorder

“…That is, only marijuana smokers (but not marijuana-naïve controls) responded to marijuana-related cues (but not neutral cues) with increased self-reported craving, and with increased craving only for marijuana but not nicotine (Lundahl and Johanson, 2011). This paradigm has been used to evaluate potential anti-craving medications for cocaine (Kranzler and Bauer, 1992;Robbins et al, 1992;Hersh et al, 1995;Berger et al, 1996;Ehrman et al, 1996;LaRowe et al, 2007;Reid and Thakkar, 2009), nicotine (Reid et al, 2007;Rohsenow et al, 2008;Franklin et al, 2011;Ditre et al, 2012), alcohol (Rohsenow et al, 2000;Hutchison et al, 2001), and marijuana (Lundahl and Greenwald, 2015). Across studies, drug-related cues reliably induced drug-specific craving despite variable efficacy of the potential medications tested.…”