We report herein that neural responses to smoking cues in the anatomically connected VS and mOFC are diminished after 3 weeks of varenicline administration and that subjective craving responses to smoking cues are also diminished. Furthermore, we show that varenicline-induced activation of the LOFC in the brain at rest predicts the blunted smoking cue–induced activity in the mOFC. Varenicline’s reciprocal actions in the reward-relevant mOFC and the reward-evaluating LOFC underlie a diminished smoking cue response and may reveal a distinctive new action that likely contributes to its clinical efficacy in smoking cessation.
We hypothesize that varenicline’s antagonistic action to block the reinforcement normally received during smoking might suppress smoking cue–elicited responses in the VS and mOFC. In support of our hypothesis, we demonstrate that varenicline significantly reduced prerandomization smoking cue–elicited craving and diminished smoking cue–induced neural responses in the VS and mOFC and in other reward-related regions. Placebo-treated smokers displayed smoking cue–induced craving at both time points and had brain responses similar to those observed prior to randomization.
Varenicline induced bilateral activation of the LOFC in the brain in the resting condition. Several lines of evidence support the theory that the OFC is involved in assimilating information on the reward value of incoming stimuli to determine the appropriate course of action, with its medial and lateral aspects subserving diverse functions.29,49
Evidence suggests a functional segregation of the OFC’s role in goal-directed behavior such that when reward value is low, as in a sated condition, processing is evident in the LOFC. In contrast, when reward value is high, as in a deprived condition, processing in the medial portion of the OFC is prominent.32,33
The results of our study extend hypotheses of 2 separate motivational systems within the OFC: the medial-portion– orchestrating approach and the lateral-portion avoidance behaviors.32
Given that varenicline reduces the reinforcement received from smoking and that subjects had smoked immediately prior to scanning, the role of the LOFC here may be to reevaluate and devalue the previous appetitive conditioned motivational properties of smoking-associated stimuli.
Given the role of the LOFC in reward-processing and decision making,49
we hypothesize that the varenicline-induced increased activity in the LOFC in the resting condition may account for the attenuated cue-induced responses in the mOFC. We observed an inverse relationship between resting-baseline activation in the LOFC and cue responses in the mOFC (ie, increased LOFC activity in the brain at rest predicted decreased mOFC responses during exposure to smoking cues). These results are important in and of themselves as they elucidate the neural correlates underlying varenicline’s action to diminish smoking cue reactivity. They also have broader implications, because the perfusion fMRI cue-reactivity pre- and postmedication model employed here may potentially be used as a screening tool to examine the likelihood of the effectiveness of promising candidate smoking cessation medications in reducing cue reactivity, prior to investing in arduous and expensive treatment trials. Although varenicline is clinically effective in preventing relapse, it aids only a subgroup of individuals; thus, knowledge of the underlying mechanism is crucial because it will guide the development of future, more effective interventions for cue-vulnerable individuals.
Because varenicline is an effective smoking cessation agent, one might speculate that the varenicline-treated group would either spontaneously quit smoking or reduce the number of cigarettes they smoked per day. No subjects in either group quit smoking, and the level of cigarette dependence and the number of cigarettes smoked per day were not different between varenicline- and placebo-treated groups at time 2. However, the varenicline group did show a significant reduction in number of cigarettes smoked per day from time 1 to time 2. Furthermore, there is considerable variability in human smoking behavior (ie, puff duration, puff volume, puff interval, and vent blocking), and it is highly probable that varenicline- and placebo-treated smokers differed in the actual amount of nicotine and other tobacco constituents that were consumed over the course of the medication regimen. Because all subjects smoked a cigarette prior to the scanning sessions, we feel that any potential differences in smoking behavior were minimized and that any residual effects are unrelated to our major finding of varenicline-induced reductions in smoking cue reactivity. Smoking immediately prior to scanning also served to minimize withdrawal, which facilitated achieving our overarching goal: to examine varenicline’s effects on cue reactivity independent of its known effects on withdrawal reduction. Given the absence of differences between the items of the S-J withdrawal scale, administered before and after exposure to smoking cues (at both time points), we assert that the observed effects of varenicline were specific to exposure to smoking cues and not to either withdrawal or changes in smoking behavior.
We observed correlative relationships between craving and brain activity in the VS and mOFC, which may be expected given the role of these regions in reward-related behavior. And, as in our first study,23
at both time points, we observed a correlative relationship between craving and activation in the posterior cingulate cortex, a region that is beginning to attract attention in the addiction literature, albeit its role is still unclear.3
The congruence between our earlier studies and this one implicating the posterior cingulate as a substrate mediating subjective craving may be fortuitous, because studies demonstrating correlative relationships between craving induced by drug cue exposure and brain activity are often in opposition18,22,50
or have not observed these relationships.51,52
Alternatively, as evinced by Franklin et al,22
wherein correlative relationships between brain and craving responses were found to be dopamine transporter–dependent, genetic variance may underlie the discordant and/or negative findings in the literature. Additionally, because there are caveats associated with reliance on subjective measures, the use of objective markers such as cognitive bias and/or attentional tasks to examine brain-behavioral relationships may be important.
Although brain-craving correlates vary across studies, including our own, the overall “brain” finding of enhanced responses to smoking cues in reward-relevant interconnected medial ventral aspects of the mesolimbic system is consistent across our 3 studies. These regions have also been consistently observed in cocaine, heroin, and other nicotine and sexual cues using a variety of imaging modalities.3,8–21
This congruence across studies emphasizes the power of a direct assay of brain physiology, such as fMRI, to study addiction processes. Because the brain’s response to emotionally laden processes is not completely under subjective control, and may be confounded by the ability to identify and communicate one’s emotional state, neurophysiological measures may be more direct and more sensitive than subjective measures of the same processes.53–56
Because drug cues play a key role in cigarette and other drug addiction processes, the action of varenicline to reduce cue reactivity may help explain its efficiency in reducing relapse. Varenicline is known to mitigate withdrawal symptoms and the reinforcement received during smoking.15
These actions may be more beneficial for smokers whose relapse is influenced to a greater degree by the absence of the pharmacological effects of nicotine on the brain (withdrawal). Conversely, medications that reduce the effect of exposure to smoking cues may be more beneficial to cue-vulnerable smokers. Unsuccessful smoking cessation is more prevalent in individuals with psychiatric illness,57,58
suggesting that they have greater difficulty quitting. Varenicline and other medications that can reduce both withdrawal and cue reactivity may be of special benefit to these subgroups.
As stated, varenicline’s action to blunt cue-induced reward-related activity in the medial OFC was predicted by its activation of the LOFC in the brain at rest. Although there is a large body of literature demonstrating 2 separate motivational systems within the OFC in response to natural rewards, to our knowledge, none of the studies have attempted to dissect their diverse roles in drug reward. The results of our study reveal a distinctive new action of varenicline that may contribute to its clinical efficacy. Furthermore, the discovery of the neural correlates underlying its action to diminish cue reactivity has relevance for the use of neuroimaging in the development of improved treatment strategies in cigarette and other drug addictions.