A Functional Magnetic Resonance Imaging (fMRI) Study of Cue-Induced Smoking Craving in Virtual Environments

Smokers who are exposed to smoking-related cues show cardiovascular reactivity and smoking craving compared with their responses to neutral cues, and increased cue reactivity predicts decreased likelihood of successful cessation. Several brain imaging studies suggested four candidate brain regions that might differ in gray matter volumes and densities between smokers and nonsmokers. However, in these studies, smokers were only exposed to smoking-related objects. In our pilot study utilizing a virtual reality (VR) technique, virtual environments (VEs) were more immersive and evoked smoking craving more effectively than traditionally used methods. In this study, we sought to test whether smokers could experience cue-induced smoking craving inside the MRI scanner by using the VR system. The smoking cue reactivity scenario was based in part on our preliminary task and consisted of 2D and 3D (or VE) conditions. The group mean of participants had increased activity in the prefrontal cortex (PFC), left anterior cingulate gyrus (ACC), left supplementary motor area, left uncus, right inferior temporal gyrus, right lingual gyrus, and right precuneus in the 2D condition. Areas of differential activation in the 3D condition were as follows: left superior temporal gyrus, right superior frontal gyrus, and left inferior occipital gyrus in the 3D condition. This finding is consistent with those of previous studies of nicotine craving showing PFC and ACC activation. However, in the 3D condition, the PFC including the superior frontal gyrus as well as the superior temporal gyrus, inferior occipital gyrus, and cerebellum were activated. Therefore, in the 3D condition, participants seemed to have more attention, visual balance, and coordinating movement than in the 2D condition.     

Cocaine facilitates craving via an action on sensory processing

Sensory systems play an important role in cocaine addiction, perhaps most clearly demonstrated when stimuli (‘cues’) associated via classical conditioning with the effects of the drug, trigger craving and relapse. It has been shown in previous studies that administration of cocaine can enhance evoked responses in the primary sensory cortex of experimental animals. Given that the speed of learning in classical conditioning is affected by the intensity of the conditioned stimulus (CS), and that cocaine enhances the neural representation of sensory stimuli in the primary sensory cortex in a manner similar to an increase in intensity, we hypothesise that cue-induced craving in human addicts is facilitated by the drug. In short, cocaine speeds the process that leads to craving. This hypothesis is supported by the fact that cocaine enhances sensory responses in humans and leads to an improvement in attention (the putative intermediary between enhanced sensory responses and facilitated learning). Furthermore, cocaine affects neural loci which are known to play a role in learning and facilitates classical conditioning when present during acquisition. In addition, related drugs like d-amphetamine and ecstasy (which themselves produce craving) affect sensory processing and attention, and in the case of d-amphetamine facilitate human learning. It is therefore possible that cocaine itself plays a – previously under-appreciated – role in the formation of associations between drug and drug-related environmental cues by enhancing primary sensory responses. A corollary of this is that, as with other intense CSs, the established association may be particularly resistant to extinction, potentially explaining why cues continue to elicit craving months or even years after the last cocaine use.     

Approach-bias predicts development of cannabis problem severity in heavy cannabis users: results from a prospective FMRI study

A potentially powerful predictor for the course of drug (ab)use is the approach-bias, that is, the pre-reflective tendency to approach rather than avoid drug-related stimuli. Here we investigated the neural underpinnings of cannabis approach and avoidance tendencies. By elucidating the predictive power of neural approach-bias activations for future cannabis use and problem severity, we aimed at identifying new intervention targets. Using functional Magnetic Resonance Imaging (fMRI), neural approach-bias activations were measured with a Stimulus Response Compatibility task (SRC) and compared between 33 heavy cannabis users and 36 matched controls. In addition, associations were examined between approach-bias activations and cannabis use and problem severity at baseline and at six-month follow-up. Approach-bias activations did not differ between heavy cannabis users and controls. However, within the group of heavy cannabis users, a positive relation was observed between total lifetime cannabis use and approach-bias activations in various fronto-limbic areas. Moreover, approach-bias activations in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) independently predicted cannabis problem severity after six months over and beyond session-induced subjective measures of craving. Higher DLPFC/ACC activity during cannabis approach trials, but lower activity during cannabis avoidance trials were associated with decreases in cannabis problem severity. These findings suggest that cannabis users with deficient control over cannabis action tendencies are more likely to develop cannabis related problems. Moreover, the balance between cannabis approach and avoidance responses in the DLPFC and ACC may help identify individuals at-risk for cannabis use disorders and may be new targets for prevention and treatment.     

Smoking at the workplace: effects of genetic and environmental causal accounts on attitudes toward smoking employees and restrictive policies

People hold diverse beliefs regarding the etiologies of individual and group differences in behaviors which, in turn, might affect their attitudes and behaviors. It is important to establish how perceived etiologies of smoking might affect the effectiveness of policy initiatives and prevention efforts. The present study assessed whether exposure to genetic vs. environmental accounts for smoking affects attitudes toward (a) workplace-related smoking policies and (b) smokers at the workplace. Results indicate that exposure to a genetic explanation led to stronger objections to a smoking restrictive policy compared with a non-genetic explanation. Additionally, participants in the genetic condition were more accepting of a smoker in the workplace than those in the environmental condition. Evidently, beliefs about the etiology of smoking influence a range of attitudes related to smokers and smoking-related policies.     

Intense passionate love attenuates cigarette cue-reactivity in nicotine-deprived smokers: an FMRI study

Self-expanding experiences like falling in love or engaging in novel, exciting and interesting activities activate the same brain reward mechanism (mesolimbic dopamine pathway) that reinforces drug use and abuse, including tobacco smoking. This suggests the possibility that reward from smoking is substitutable by self-expansion (through competition with the same neural system), potentially aiding cessation efforts. Using a model of self-expansion in the context of romantic love, the present fMRI experiment examined whether, among nicotine-deprived smokers, relationship self-expansion is associated with deactivation of cigarette cue-reactivity regions. Results indicated that among participants who were experiencing moderate levels of craving, cigarette cue-reactivity regions (e.g., cuneus and posterior cingulate cortex) showed significantly less activation during self-expansion conditions compared with control conditions. These results provide evidence that rewards from one domain (self-expansion) can act as a substitute for reward from another domain (nicotine) to attenuate cigarette cue reactivity.     

The role of dorsal anterior cingulate cortex in the regulation of craving by reappraisal in smokers

Rationale and Objective

Drug cues can induce craving for drugs of abuse. Dysfunctional regulation of emotion and motivation regarding rewarding objects appears to be an integral part of addiction. It has been found that cognitive strategies decreased the intensity of craving in addicts. Reappraisal strategy is a type of cognitive strategy that requires participants to reinterpret the meaning of an emotional situation. In addition, studies have found that activation of the dorsal anterior cingulate cortex (dACC) is associated with the selection and application of cognitive reappraisal. In present study, we sought to determine whether such cognitive regulation engages the dACC and improves inhibition of craving in smokers.

Methods

Sixteen smokers underwent functional magnetic resonance imaging (fMRI) during performance of a cigarette reward-conditioning procedure with cognitive reappraisal. We focused our analyses on the dACC as a key structure of cognitive control of craving. Cue induced craving under different conditions was obtained. Correlational analysis between the functional response in the dACC and the subjective craving was performed.

Results

We found that using a cognitive reappraisal was successful in decreasing the conditioned craving. Right dACC (BA 24/32) engaged in the cognitive reappraisal. In addition, the individual’s subjective craving was negatively correlated with the right dACC activation.

Conclusions

These findings suggest that the dACC are important substrates of Inhibition of cue induced craving in smokers. Cognitive regulation by cognitive reappraisal may help addicted individuals avoid the anticipated situations where they are exposed to conditioned cues.     

Relief as a reward: hedonic and neural responses to safety from pain

Relief fits the definition of a reward. Unlike other reward types the pleasantness of relief depends on the violation of a negative expectation, yet this has not been investigated using neuroimaging approaches. We hypothesized that the degree of negative expectation depends on state (dread) and trait (pessimism) sensitivity. Of the brain regions that are involved in mediating pleasure, the nucleus accumbens also signals unexpected reward and positive prediction error. We hypothesized that accumbens activity reflects the level of negative expectation and subsequent pleasant relief. Using fMRI and two purpose-made tasks, we compared hedonic and BOLD responses to relief with responses during an appetitive reward task in 18 healthy volunteers. We expected some similarities in task responses, reflecting common neural substrates implicated across reward types. However, we also hypothesized that relief responses would differ from appetitive rewards in the nucleus accumbens, since only relief pleasantness depends on negative expectations. The results confirmed these hypotheses. Relief and appetitive reward task activity converged in the ventromedial prefrontal cortex, which also correlated with appetitive reward pleasantness ratings. In contrast, dread and pessimism scores correlated with relief but not with appetitive reward hedonics. Moreover, only relief pleasantness covaried with accumbens activation. Importantly, the accumbens signal appeared to specifically reflect individual differences in anticipation of the adverse event (dread, pessimism) but was uncorrelated to appetitive reward hedonics. In conclusion, relief differs from appetitive rewards due to its reliance on negative expectations, the violation of which is reflected in relief-related accumbens activation.     

Smoking among Yale medical school faculty

A 1985 survey of a random sample of faculty at the Yale University School of Medicine investigated smoking prevalence and attitudes. The overall prevalence of cigarette smoking was estimated to be 9.8 percent, much lower than the prevalence in the general population. A higher proportion of women than men were current cigarette smokers. With regard to department affiliation, surgeons were most frequently current cigarette smokers, with psychiatrists having the lowest prevalence of current cigarette smoking and the highest percentage of people who had never smoked. In general, attitudes toward smoking were negative.     

Factors Associated with Tobacco Smoking and Cessation among HIV-Infected Individuals under Care in Rio de Janeiro,Brazil

Worldwide the prevalence of smoking among people living with HIV/AIDS is elevated compared to the general population. This probably reflects the cluster of individual characteristics that have shared risk factors for HIV infection and smoking. A cross-sectional study, enrolling a convenience sample from a Brazilian HIV clinical cohort was conducted to evaluate the prevalence of tobacco smoking and the factors associated with current smoking and abstinence. A total of 2,775 HIV-infected individuals were interviewed: 46.2% have never smoked, 29.9% were current smokers and 23.9% were former smokers. Current smokers had a higher prevalence of alcohol and illicit drug use when compared to the other two groups. A higher proportion of heterosexual individuals were former smokers or never smokers while among men who have sex with men (MSM) a higher proportion were current smokers. Former smokers had been more frequently diagnosed with high blood pressure, diabetes mellitus, cardiovascular diseases and depression, while for current smokers lung diseases were more frequent. Former smokers and current smokers were more likely to have had any hospital admission (42.0% and 41.2%, respectively) than participants who never smoked (33.5%) (p<0.001). Multivariate model results showed that current smokers (versus never smokers) were more likely to be less educated, to report the use of alcohol, crack and cocaine and to present clinical comorbidities. Former smokers (versus current smokers) were more likely to be older, to have smoked for a shorter amount of time and to have smoked >31 cigarettes/day. MSM (compared to heterosexuals) and cocaine users (versus non-users) had lower odds of being former smokers. Considering our results, smoking cessation interventions should be tailored to younger individuals, MSM and substance users.     

Gaze Duration Biases for Colours in Combination with Dissonant and Consonant Sounds: A Comparative Eye-Tracking Study with Orangutans

Research on colour preferences in humans and non-human primates suggests similar patterns of biases for and avoidance of specific colours, indicating that these colours are connected to a psychological reaction. Similarly, in the acoustic domain, approach reactions to consonant sounds (considered as positive) and avoidance reactions to dissonant sounds (considered as negative) have been found in human adults and children, and it has been demonstrated that non-human primates are able to discriminate between consonant and dissonant sounds. Yet it remains unclear whether the visual and acoustic approach–avoidance patterns remain consistent when both types of stimuli are combined, how they relate to and influence each other, and whether these are similar for humans and other primates. Therefore, to investigate whether gaze duration biases for colours are similar across primates and whether reactions to consonant and dissonant sounds cumulate with reactions to specific colours, we conducted an eye-tracking study in which we compared humans with one species of great apes, the orangutans. We presented four different colours either in isolation or in combination with consonant and dissonant sounds. We hypothesised that the viewing time for specific colours should be influenced by dissonant sounds and that previously existing avoidance behaviours with regard to colours should be intensified, reflecting their association with negative acoustic information. The results showed that the humans had constant gaze durations which were independent of the auditory stimulus, with a clear avoidance of yellow. In contrast, the orangutans did not show any clear gaze duration bias or avoidance of colours, and they were also not influenced by the auditory stimuli. In conclusion, our findings only partially support the previously identified pattern of biases for and avoidance of specific colours in humans and do not confirm such a pattern for orangutans.     

Relatively strong automatic appetitive action-tendencies in male carriers of the OPRM1 G-allele

This study investigated whether automatic approach action tendencies for alcohol-related stimuli were associated with variation in the mu-opioid receptor gene ( OPRM1 ), previously related to rewarding effects of alcohol and craving. An adapted approach avoidance task was used, in which participants pulled or pushed a joystick in reaction to the format of a picture shown on the computer screen (e.g. pull landscape pictures and push portrait pictures). Picture size on the screen changed upon joystick movement, so that upon a pull movement picture size increased (creating a sense of approach) and upon a push movement picture size decreased (avoidance). Participants reacted to four categories of pictures: alcohol-related, other appetitive, general positive and general negative. The sample consisted of 84 heavy drinking young men without a g-allele in the A118G (or A355G) single nucleotide polymorphism of the OPRM1 gene and 24 heavy drinking young men with at least one g-allele. Heavy drinking carriers of a g-allele showed relatively strong automatic approach tendencies for alcohol (approach bias). Unexpectedly, they also showed an approach bias for other appetitive stimuli. No approach bias was found for general positive or negative stimuli. These results suggest that automatic approach tendencies in response to appetitive stimuli could play a role in the etiology of addictive behaviors and related disorders. Further research is needed to investigate the specificity of this approach bias and possible gender differences.     

On the Relevance of Natural Stimuli for the Study of Brainstem Correlates: The Example of Consonance Perception

Some combinations of musical tones sound pleasing to Western listeners, and are termed consonant, while others sound discordant, and are termed dissonant. The perceptual phenomenon of consonance has been traced to the acoustic property of harmonicity. It has been repeatedly shown that neural correlates of consonance can be found as early as the auditory brainstem as reflected in the harmonicity of the scalp-recorded frequency-following response (FFR). “Neural Pitch Salience” (NPS) measured from FFRs—essentially a time-domain equivalent of the classic pattern recognition models of pitch—has been found to correlate with behavioral judgments of consonance for synthetic stimuli. Following the idea that the auditory system has evolved to process behaviorally relevant natural sounds, and in order to test the generalizability of this finding made with synthetic tones, we recorded FFRs for consonant and dissonant intervals composed of synthetic and natural stimuli. We found that NPS correlated with behavioral judgments of consonance and dissonance for synthetic but not for naturalistic sounds. These results suggest that while some form of harmonicity can be computed from the auditory brainstem response, the general percept of consonance and dissonance is not captured by this measure. It might either be represented in the brainstem in a different code (such as place code) or arise at higher levels of the auditory pathway. Our findings further illustrate the importance of using natural sounds, as a complementary tool to fully-controlled synthetic sounds, when probing auditory perception.     

The Neural Mechanisms Underlying the Acute Effect of Cigarette Smoking on Chronic Smokers

Although previous research had related structural changes and impaired cognition to chronic cigarette smoking, recent neuroimaging studies have associated nicotine, which is a main chemical substance in cigarettes, with improvements in cognitive functions (e.g. improved attention performance). However, information about the alterations of whole-brain functional connectivity after acute cigarette smoking is limited. In this study, 22 smokers underwent resting-state functional magnetic resonance imaging (rs-fMRI) after abstaining from smoking for 12 hours (state of abstinence, SOA). Subsequently, the smokers were allowed to smoke two cigarettes (state of satisfaction, SOS) before they underwent a second rs-fMRI. Twenty non-smokers were also recruited to undergo rs-fMRI. In addition, high-resolution 3D T1-weighted images were acquired using the same magnetic resonance imaging(fMRI)scanner for all participants. The results showed that smokers had structural changes in insula, thalamus, medial frontal cortex and several regions of the default mode network (DMN) compared with non-smokers. Voxel-wise group comparisons of newly developed global brain connectivity (GBC) showed that smokers in the SOA condition had higher GBC in the insula and superior frontal gyrus compared with non-smokers. However, smokers in the SOS condition demonstrated significantly lower GBC in several regions of the DMN, as compared with smokers in the SOA condition. These results suggest that structural integrity combined with dysfunction of the DMN might be involved in relapses after a short period of time among smokers.     

Alcohol Use Disorder with and without Stimulant Use: Brain Morphometry and Its Associations with Cigarette Smoking,Cognition, and Inhibitory Control

Objective

Little is known about the effects of polysubstance use and cigarette smoking on brain morphometry. This study examined neocortical brain morphometric differences between abstinent polysubstance dependent and alcohol-only dependent treatment seekers (ALC) as well as light drinking controls (CON), the associations of cigarette smoking in these polysubstance users (PSU), and morphometric relationships to cognition and inhibitory control.

Methods

All participants completed extensive neuropsychological assessments and 4 Tesla brain magnetic resonance imaging. PSU and ALC were abstinent for one month at the time of study. Parcellated morphological data (volume, surface area, thickness) were obtained with FreeSurfer methodology for the following bilateral components: dorso-prefrontal cortex (DPFC), anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and insula. Regional group differences were examined and structural data correlated with domains of cognition and inhibitory control.

Results

PSU had significantly smaller left OFC volume and surface area and trends to smaller right DPFC volume and surface area compared to CON; PSU did not differ significantly from ALC on these measures. PSU, however, had significantly thinner right ACC than ALC. Smoking PSU had significantly larger right OFC surface area than non-smoking PSU. No significant relationships between morphometry and quantity/frequency of substance use, alcohol use, or age of onset of heavy drinking were observed. PSU exhibited distinct relationships between brain structure and processing speed, cognitive efficiency, working memory and inhibitory control that were not observed in ALC or CON.

Conclusion

Polysubstance users have unique morphometric abnormalities and structure-function relationships when compared to individuals dependent only on alcohol and light drinking controls. Chronic cigarette smoking is associated with structural brain irregularities in polysubstance users. Further elucidation of these distinctive characteristics could help inform the development of targeted and thus potentially more effective treatments in this large but understudied population.     

Obesity and Smoking: Comparing Cessation Treatment Seekers With the General Smoking Population

Obesity and smoking represent the leading preventable causes of morbidity and mortality in the United States. This study compared the prevalence of obesity among smokers seeking cessation treatment (n = 1,428) vs. a general population (n = 4,081) of never smokers, former smoker, and current smokers. Data from treatment‐seeking smokers in the Wisconsin Smokers' Health Study (WSHS) and individuals who completed the National Health and Nutrition Examination Survey (NHANES) 2005–2006 were pooled and obesity rates and other health characteristics were compared. The prevalence of obesity was significantly higher among WSHS treatment‐seeking smokers (36.8%) vs. NHANES current smokers (29.6%), but the obesity rates of WSHS treatment‐seeking smokers did not differ from NHANES former smokers (36.5%) or never smokers (36.5%). Treatment‐seeking smokers were more likely to be female and to have higher educational attainment compared to NHANES participants. Analysis of health characteristics revealed that treatment‐seeking smokers had higher levels of dietary fiber and vitamin C and lower blood levels of total cholesterol, triglycerides, and fasting glucose compared to NHANES current smokers. Results suggest that treatment‐seeking smokers may have a different health profile than current smokers in the general population. Health care providers should be aware of underlying heath issues, particularly obesity, in patients seeking smoking cessation treatment.     

Prefrontal norepinephrine determines attribution of "high" motivational salience

Intense motivational salience attribution is considered to have a major role in the development of different psychopathologies. Numerous brain areas are involved in "normal" motivational salience attribution processes; however, it is not clear whether common or different neural mechanisms also underlie intense motivational salience attribution. To elucidate this a brain area and a neural system had to be envisaged that were involved only in motivational salience attribution to highly salient stimuli. Using intracerebral microdialysis, we found that natural stimuli induced an increase in norepinephrine release in the medial prefrontal cortex of mice proportional to their salience, and that selective prefrontal norepinephrine depletion abolished the increase of norepinephrine release in the medial prefrontal cortex induced by exposure to appetitive (palatable food) or aversive (light) stimuli independently of salience. However, selective norepinephrine depletion in the medial prefrontal cortex impaired the place conditioning induced exclusively by highly salient stimuli, thus indicating that prefrontal noradrenergic transmission determines approach or avoidance responses to both reward- and aversion-related natural stimuli only when the salience of the unconditioned natural stimulus is high enough to induce sustained norepinephrine outflow. This affirms that prefrontal noradrenergic transmission determines motivational salience attribution selectively when intense motivational salience is processed, as in conditions that characterize psychopathological outcomes.     

Preference for consonant music over dissonant music by an infant chimpanzee

It has been shown that humans prefer consonant sounds from the early stages of development. From a comparative psychological perspective, although previous studies have shown that birds and monkeys can discriminate between consonant and dissonant sounds, it remains unclear whether nonhumans have a spontaneous preference for consonant music over dissonant music as humans do. We report here that a five-month-old human-raised chimpanzee (Pan troglodytes) preferred consonant music. The infant chimpanzee consistently preferred to produce, with the aid of our computerized setup, consonant versions of music for a longer duration than dissonant versions. This result suggests that the preference for consonance is not unique to humans. Further, it supports the hypothesis that one major basis of musical appreciation has some evolutionary origins.     

Bitter substances suppress afferent responses to an appetitive mixture: evidence for peripheral integration of chemosensory stimuli.

The processes that lead from detection of chemicals, transduction, and coding with the appropriate message to initiate ingestion of a palatable meal or to reject a potentially noxious substance are poorly understood in vertebrates owing to the complex organization of the taste system. As a first step in elucidating the cellular basis of the behavioral differences elicited by appetitive stimuli and bitter compounds, we recorded from the afferent nerves conveying peripheral chemosensory information to the CNS in the head of the leech, Hirudo medicinalis. Superfusion of the chemosensory region of the lip of Hirudo with a mixture of NaCl (150 mM) and arginine (1 mM), an appetitive solution that elicits ingestion, increased the neuronal activity in the afferent cephalic nerves, for example (Zhang X, Wilson RJ, Li Y, Kleinhaus AL. 2000. Chemical and thermal stimuli have short-lived effects on the Retzius cell in the medicinal leech. J Neurobiol 43:304-311.). In the present paper we show that superfusing the lip with quinine or denatonium reduced the basal neural activity in the afferents. Furthermore, these bitter substances in the appetitive solution counteracted the increased activity the appetitive solution evoked in the cephalic nerves. Thus, the neural activity evoked by the application of appetitive and aversive stimuli to the chemosensory area of the lip paralleled the opposite behavioral responses to the same chemicals. The results suggest that individual leech taste cells possess receptors for both types of stimuli. Therefore, the leech may be a good model system in which to study peripheral taste events in cells that may possess multiple receptors and transduction mechanisms that interact to integrate information.     

Genetic Variants and Early Cigarette Smoking and Nicotine Dependence Phenotypes in Adolescents

Background

While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes.

Methods

In a prospective study of 1294 adolescents aged 12–13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7–8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator).

Results

The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076.

Conclusions

Because the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3).

Impact

Dopaminergic pathways may be salient during early smoking and the development of ND.