We report a strong association between MOR availability in the amygdala and motivation to smoke to relieve negative affect. However, contrary to our expectation, there were no significant changes in affect related to smoking the cigarettes prior to the scans, nor was the degree of change in negative affect after smoking related to MOR availability. Thus, we find that a general, pre-existing motivation for smoking relates to MOR binding availability, but that the experience of smoking, at least in this setting, does not.
Our finding of a positive correlation between MOR availability in the amygdala and motivation to smoke for negative affect relief is consistent with prior literature documenting the role of the µ-opioid receptor in both affect regulation and motivational behavior. The association of MOR availability in the amygdala with affective motives to smoke is consistent with functional neuroimaging evidence for a role of the amygdala in processing and regulating affective responses (Davidson and Irwin 1999
; Diekhof et al. 2011
; Kim et al. 2011
). The amygdala is highly connected to cortical structures throughout the brain and is important in the integration and regulation of emotional responses (Pessoa 2010
). Opioid neurotransmission in the amygdala has been implicated in assigning motivational salience to reward cues in rats (Mahler and Berridge 2009
), and in humans changes in MOR availability are associated with emotional responses to stimuli (Ribeiro et al. 2005
; Zubieta et al. 2003
). Other than our previous report on this sample (Ray et al. 2011
), only one other study has used PET imaging to examine acute effects of smoking on MOR availability (Scott et al. 2007
). Scott and colleagues found a significant increase in MOR availability from the denicotinized to the nicotine condition, and the increase in MOR availability in the amygdala was related to decreased craving scores, but not to mood measures. Although we did administer a two-item craving questionnaire to participants before and after smoking the cigarettes, changes in craving were not related to MOR availability in our sample (data not shown). However, the differing results between these two studies may likely be attributed to differences in study design, including study population (6 male smokers in the prior study versus 22 smokers of both genders in the current study), number of cigarettes smoked in each condition (two cigarettes 10 minutes apart versus a single pre-scan cigarette), and nicotine yield of the nicotine cigarette (1.01 mg versus 0.6 mg).
There are several potential interpretations of finding an association of MOR availability in the amygdala with smoking motivation but not with actual mood change after smoking a cigarette, suggesting future avenues of investigation. It is possible that those individuals with greater MOR availability may have experienced greater negative affect relief early in their smoking experience, and that the belief that cigarette smoking reduced negative affect persisted despite the development of tolerance to pharmacological effects of nicotine. In support of this, adolescents with higher expectancies for negative affect relief from smoking do report greater reductions of negative affect after smoking (Colvin and Mermelstein 2010
), whereas expectancies for negative affect relief are not related to actual changes in negative affect in adult smokers (Perkins et al. 2011
). Another potential explanation may relate to our use of research cigarettes yielding 0.6 mg of nicotine for the “nicotine cigarette” session, which was lower than the mean yield of our participants’ preferred brands (mean 1.1 mg, SD 0.5 mg). Prior studies have shown that low-nicotine cigarettes are rated as lower quality and less satisfying than participants’ preferred brands (Benowitz et al. 2006
; Strasser et al. 2007
). It is possible that the research cigarettes were less rewarding than the participants’ usual brand, and thus did not affect mood in the same fashion. In addition, even the denicotinized cigarette contains minute amounts of nicotine; Brody and colleagues (2009)
found that smoking a denicotinized cigarette results in reduced, but still significant, activation of α4β2 nicotinic receptors, which may explain why the smoking manipulation in the current study had no effect. Alternatively, there is evidence to suggest that effects of smoking on mood may derive more from the sensory effects or ritual of smoking than from nicotine (Juliano et al. 2011
; Perkins et al. 2008
; Rose 2006
). Our paced puffing procedure, although necessary to standardize nicotine exposure, did not allow participants to smoke at their own pace or to smoke to satiety, and thus may have affected mood differently than self-regulated smoking. Future investigations into smoking-related mood effects may benefit from assessments of mood change in a naturalistic environment using the participants’ preferred cigarettes.
Another possibility to consider is that it is µ-opioid system regulation of reward, rather than mood change, which drives the motivation to smoke to relieve negative affect. There is a growing body of literature suggesting that although smokers expect improvements in mood after smoking a cigarette, smoking does not reliably relieve negative affect due to anything other than nicotine withdrawal (Conklin and Perkins 2005
; Perkins et al. 2010
). Indeed, the absence of significant mood change in our study is consistent with this literature. However, a common polymorphism in the gene encoding the µ-opioid receptor (OPRM1
A118G) is associated with the relative reinforcing value of nicotine (Perkins et al. 2008
; Ray et al. 2006
). Interestingly, the A allele, which we previously demonstrated was associated with greater MOR availability in this sample (Ray et al. 2011
), has also been associated with increased cigarette reward during negative versus positive mood (Perkins et al. 2008
) as well as with increased reinforcement learning compared to G allele carriers (Lee et al. 2011
). It is possible that even though smoking is not effective in actually relieving negative mood, smokers with greater MOR availability find cigarettes more rewarding under these circumstances and are more likely to develop a conditioned association between smoking and negative mood.
There are a few limitations which should be considered within our study. The NAR scale is a self-report measure and relies on accurate self-assessment of motivation rather than objective observation; however, this measure has been shown to correlate significantly with self-monitored smoking data (Shiffman and Prange 1988
; Tate and Stanton 1990
). Mean NAR scores in this study were lower than scores for non-depressed smokers in previous studies (Lerman et al. 1996
; Lerman et al. 1998
). This may be related to oversampling for OPRM1
*/G genotype, which has been associated with reduced subjective nicotine reward (Ray et al. 2011
) and reduced reinforcement learning (Lee et al. 2011
). Also due to oversampling of OPRM1
*/G, the distribution of OPRM1
genotypes in our sample is not representative of the normal smoking population. Smokers of menthol cigarettes were excluded from the study; therefore caution should be used when extrapolating to general smoking populations. We did not use a smoking topography device to measure puff volume or assess plasma nicotine levels at either session. Our use of a standardized puffing procedure mitigates differences in puff volume between smokers (Strasser et al. 2005a
), and significant differences in plasma nicotine levels are obtained when smoking Quest® denicotinized cigarettes compared to the 0.6 mg cigarettes (Brody et al. 2009
). Other studies have shown variation in MOR availability and in µ-opioid system response to stimuli between males and females (Zubieta et al. 1999
; Zubieta et al. 2002
). The number of female smokers included in the current study was too small to test for sex heterogeneity; however, sex was included as a covariate in all models and did not predict MOR availability. Finally, as with any PET imaging study, the reported binding potentials do not distinguish between number of available receptors, receptor affinity or endogenous opioid tone.
In conclusion, we have demonstrated a significant association of MOR availability in the amygdala with motivation to smoke to relieve negative affect; furthermore, this motivation was inconsistent with the actual experience of smoking. These data offer a potential biological mechanism underlying this particular smoking motive, and add to a growing body of literature highlighting inconsistencies between smokers’ expectations and real-time effects of smoking. Further research into the biological mechanisms influencing affective response to smoking and motivation to smoke may be useful in effecting improvements in smoking cessation treatment.