Riju Ray

Effects of the α4β2 Partial Agonist Varenicline on Brain Activity and Working Memory in Abstinent Smokers

BACKGROUND Cognitive alterations are a core symptom of nicotine withdrawal, contributing to smoking relapse. In rodents and humans, cognitive deficits can be reversed by treatment with the alpha4beta2 nicotinic receptor partial agonist varenicline. This neuroimaging study examined the neural mechanisms that underlie these effects. METHODS Twenty-two smokers completed 13 days of varenicline and placebo treatment in a double-blind crossover study with two functional magnetic resonance imaging sessions: after 3 days of abstinence while on varenicline and after 3 days of abstinence while on placebo (counterbalanced randomized order, 2-week washout). Blood oxygenation level-dependent (BOLD) data were acquired during performance of a visual N-back working memory task. RESULTS In a region of interest analysis, significant effects of treatment on mean percent signal change (varenicline > placebo) were observed in the dorsal anterior cingulate/medial frontal cortex, left dorsolateral prefrontal cortex, and right dorsolateral prefrontal cortex. In a cross-region model, there was a significant interaction of treatment by memory load, indicating significant increases in BOLD signal for varenicline versus placebo at the 2-back and 3-back levels but not the 1-back level. Varenicline improved performance (correct response time) in highly dependent smokers with no effect among less dependent smokers. In highly dependent smokers, faster correct response time was associated with increased BOLD signal. CONCLUSIONS This study provides novel evidence that the alpha4beta2 partial agonist varenicline increases working memory-related brain activity after 3 days of nicotine abstinence, particularly at high levels of task difficulty, with associated improvements in cognitive performance among highly dependent smokers.

Human Mu Opioid Receptor (OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers

Evidence points to the endogenous opioid system, and the mu-opioid receptor (MOR) in particular, in mediating the rewarding effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the human MOR gene (OPRM1 A118G) has been shown to alter receptor protein level in preclinical models and smoking behavior in humans. To clarify the underlying mechanisms for these associations, we conducted an in vivo investigation of the effects of OPRM1 A118G genotype on MOR binding potential (BPND or receptor availability). Twenty-two smokers prescreened for genotype (12 A/A, 10 */G) completed two [11C]carfentanil positron emission tomography (PET) imaging sessions following overnight abstinence and exposure to a nicotine-containing cigarette and a denicotinized cigarette. Independent of session, smokers homozygous for the wild-type OPRM1 A allele exhibited significantly higher levels of MOR BPND than smokers carrying the G allele in bilateral amygdala, left thalamus, and left anterior cingulate cortex. Among G allele carriers, the extent of subjective reward difference (denicotinized versus nicotine cigarette) was associated significantly with MOR BPND difference in right amygdala, caudate, anterior cingulate cortex, and thalamus. Future translational investigations can elucidate the role of MORs in nicotine addiction, which may lead to development of novel therapeutics.

Effect of abstinence challenge on brain function and cognition in smokers differs by COMT genotype

The val allele of the catechol-O-methyltransferase (COMT) val158met polymorphism has been linked with nicotine dependence and with cognitive performance in healthy volunteers. We tested the hypothesis that the val allele is a risk factor for altered brain function and cognition during nicotine abstinence as compared with the normal smoking state. Chronic smokers (n=33) were genotyped prospectively for the COMT polymorphism for balanced selection of met/met, val/met and val/val groups. A visual N-back working memory task was performed during two separate blood oxygen level-dependent (BOLD) functional magnetic resonance imaging sessions in counterbalanced order: (1) smoking as usual, and (2)⩾14 h confirmed abstinence. Significant genotype by session interactions were observed for BOLD signal in right dorsolateral prefrontal cortex (DLPFC; (P=0.0005), left DLPFC (P=0.02) and dorsal cingulate/medial prefrontal cortex (P=0.01) as well as for task reaction time (P=0.03). Smokers with val/val genotypes were more sensitive to the abstinence challenge than carriers of the met allele, with the greatest effects on BOLD signal and performance speed at the highest working memory load. These data suggest a novel brain–behavior mechanism that may underlie the increased susceptibility to nicotine dependence and smoking relapse associated with the COMT val allele. Exploration of the effects of COMT inhibitors as a possible smoking cessation aid in this group may be warranted.

Nicotine Dependence: Biology, Behavior, and Treatment

Despite great advances in the understanding and treatment of nicotine dependence, close to 21% of adults in the United States continue to smoke. Tobacco use is the single greatest cause of premature and preventable death in the United States. This article reviews the epidemiology, assessment, neurobiology, genetic etiology, and treatment of nicotine dependence. Enhanced understanding of these dimensions of nicotine dependence may help to advance progress toward lowering the prevalence rate of tobacco use in the U.S. and lowering the rate of tobacco-related morbidity and mortality.

Identification of pharmacogenetic markers in smoking cessation therapy.

Pharmacogenetic clinical trials seek to identify genetic modifiers of treatment effects. When a trial has collected data on many potential genetic markers, a first step in analysis is to screen for evidence of pharmacogenetic effects by testing for treatment‐by‐marker interactions in a statistical model for the outcome of interest. This approach is potentially problematic because (i) individual significance tests can be overly sensitive, particularly when sample sizes are large; and (ii) standard significance tests fail to distinguish between markers that are likely, on biological grounds, to have an effect, and those that are not. One way to address these concerns is to perform Bayesian hypothesis tests [Berger (1985) Statistical decision theory and Bayesian analysis. New York: Springer; Kass and Raftery (1995) J Am Stat Assoc 90:773–795], which are typically more conservative than standard uncorrected frequentist tests, less conservative than multiplicity‐corrected tests, and make explicit use of relevant biological information through specification of the prior distribution. In this article we use a Bayesian testing approach to screen a panel of genetic markers recorded in a randomized clinical trial of bupropion versus placebo for smoking cessation. From a panel of 59 single‐nucleotide polymorphisms (SNPs) located on 11 candidate genes, we identify four SNPs (one each on CHRNA5 and CHRNA2 and two on CHAT) that appear to have pharmacogenetic relevance. Of these, the SNP on CHRNA5 is most robust to specification of the prior. An unadjusted frequentist test identifies seven SNPs, including these four, none of which remains significant upon correction for multiplicity. In a panel of 43 randomly selected control SNPs, none is significant by either the Bayesian or the corrected frequentist test.

Genetic variation in mu-opioid-receptor-interacting proteins and smoking cessation in a nicotine replacement therapy trial

Extending a previous finding of an association between functional genetic variation in the mu-opioid receptor gene and response to nicotine replacement therapy, we explored the role of genetic variants in two genes encoding mu-opioid-receptor-interacting proteins, namely ARRB2 and HINT1. Participants were 374 smokers treated for nicotine dependence with either transdermal nicotine or nicotine nasal spray for 8 weeks in an open-label randomized trial. In a logistic regression model controlling for OPRM1 genotype, treatment type, and other covariates, we found no significant main effect of ARRB2 genotype on abstinence at either end of treatment or 6-month follow-up. Participants with the HINT1 TT genotype had significantly higher abstinence rates at 6-month follow-up, but this may not be a pharmacogenetic effect, given that the participants were drug free during this time. Haplotype analysis did not reveal any significant associations for either gene. We found an interaction of ARRB2 and OPRM1 genotype on abstinence at 6 months that approached significance; however, interpretation of this finding is limited by the small number of participants with the minor alleles for both genes. Although these data do not provide support for the role of genetic variation in these mu-opioid-receptor-interacting proteins and smoking cessation, further exploration of opioid pathway genes in larger prospective pharmacogenetic trials may be warranted.

Convergent Evidence that Choline Acetyltransferase Gene Variation is Associated with Prospective Smoking Cessation and Nicotine Dependence

The ability to quit smoking is heritable, yet few genetic studies have investigated prospective smoking cessation. We conducted a systems-based genetic association analysis in a sample of 472 treatment-seeking smokers of European ancestry after 8 weeks of transdermal nicotine therapy for smoking cessation. The genotyping panel included 169 single-nucleotide polymorphisms (SNPs) in 7 nicotinic acetylcholine receptor subunit genes and 4 genes in the endogenous cholinergic system. The primary outcome was smoking cessation (biochemically confirmed) at the end of treatment. SNPs clustered in the choline acetyltransferase (ChAT) gene were individually identified as nominally significant, and a 5-SNP haplotype (block 6) in ChAT was found to be significantly associated with quitting success. Single SNPs in ChAT haplotype block 2 were also associated with pretreatment levels of nicotine dependence in this cohort. To replicate associations of SNPs in haplotype blocks 2 and 6 of ChAT with nicotine dependence in a non-treatment-seeking cohort, we used data from an independent community-based sample of 629 smokers representing 200 families of European ancestry. Significant SNP and haplotype associations were identified for multiple measures of nicotine dependence. Although the effect sizes in both cohorts are modest, converging data across cohorts and phenotypes suggest that ChAT may be involved in nicotine dependence and ability to quit smoking. Additional sequencing and characterization of ChAT may reveal functional variants that contribute to nicotine dependence and smoking cessation.

Nicotine abstinence-induced cerebral blood flow changes by genotype

This study explored whether functional genetic variants previously associated with nicotine dependence are associated with regional cerebral blood flow (rCBF) changes during nicotine abstinence (compared to satiety; smoking as usual). Thirteen smokers participating in a prior arterial spin labeled (ASL) perfusion MRI study were scanned on two occasions (after >12h abstinence vs. satiety), and were genotyped for variants in the dopamine D2 receptor (DRD2-141 Ins/DelC; DRD2 C957T); a dopamine metabolizing enzyme (COMT val(158) met), and the mu opioid receptor (OPRM1 A118G). Significantly greater CBF increases were found in regions previously linked with cigarette cravings among carriers of the DelC variant of DRD2-141 and among the COMT val/val group. Smokers with TT genotypes for the DRD2 C957T exhibited less change in rCBF in abstinence relative to satiety, compared to those with CC or CT genotypes. Finally, smokers with OPRM1 AA genotypes showed significant increases in CBF in regions associated previously with cigarette cravings. While preliminary, these results suggest a neural mechanism through which these genetic variants may be linked with nicotine dependence, and provide further support for increased biological vulnerability in these subgroups of smokers.

Cost-effectiveness of pharmacogenetic testing to tailor smoking-cessation treatment

We evaluated the cost-effectiveness of a range of smoking cessation drug treatments, including varenicline, transdermal nicotine (TN), bupropion and the use of a genetic test to choose between TN and bupropion. We performed Monte Carlo simulation with sensitivity analysis, informing analyses with published estimates of model parameters and current prices for genetic testing and smoking-cessation therapy. The primary outcomes were discounted life-years (LY) and lifetime tobacco-cessation treatment costs. In the base case, varenicline treatment was optimal with an ICER, compared to bupropion, of

Neuroimaging, genetics and the treatment of nicotine addiction.

2985/LY saved. In sensitivity analyses, varenicline was in all cases (and bupropion in most cases) admissible; only under favorable assumptions was the genetically tailored approach competitive. Our data suggest that an untailored approach of treatment with either bupropion or varenicline is a cost-effective form of tobacco dependence treatment, but a tailored approach for selecting between TN and bupropion can be cost-effective under plausible assumptions.