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author:("Ray, riu")
1.  Evidence from Mouse and Man for a Role of Neuregulin 3 in Nicotine Dependence 
Molecular psychiatry  2013;19(7):801-810.
Addiction to nicotine and ability to quit smoking are influenced by genetic factors. We used functional genomic approaches (chromatin immunoprecipitation (ChIP) and whole genome sequencing) to identify CREB targets following chronic nicotine administration and withdrawal in rodents. fWe found that chronic nicotine and withdrawal differentially modulate CREB binding to the gene for Neuregulin 3 (NRG3). Quantitative analysis of saline, nicotine, and nicotine withdrawal in two biological replicates corroborate this finding, with NRG3 increases in both mRNA and protein following withdrawal from chronic nicotine treatment. To translate these data for human relevance, single nucleotide polymorphisms (SNPs) across NRG3 were examined for association with prospective smoking cessation among smokers of European ancestry treated with transdermal nicotine in two independent cohorts. Individual SNP and haplotype analysis support association of NRG3 SNPs and smoking cessation success. NRG3 is a neural-enriched member of the EGF family, and a specific ligand for the receptor tyrosine kinase ErbB4, which is also up-regulated following nicotine treatment and withdrawal. Mice with significantly reduced levels of NRG3 or pharmacological inhibition of ErbB4 show similar reductions in anxiety following nicotine withdrawal compared to control animals, suggesting a role for NRG3 in nicotine dependence. While the function of the SNP in NRG3 in humans is not known, these data suggest that Nrg3/ErbB4 signaling may be an important factor in nicotine dependence.
doi:10.1038/mp.2013.104
PMCID: PMC3877725  PMID: 23999525
mouse; human; single nucleotide polymorphism (SNP); ChIP-Seq; neuregulin 3 (NRG3); nicotine; smoking cessation
2.  Cognitive effects of the acetylcholinesterase inhibitor, donepezil, in healthy, non-treatment seeking smokers: A pilot feasibility study 
Drug and alcohol dependence  2012;126(1-2):263-267.
Background
There is a need to identify medications to aid in smoking cessation. Reducing withdrawal-related cognitive deficits represents a pharmacological target for new pharmacotherapies. Endogenous acetylcholine levels, which are modulated by acetylcholinesterase inhibitors (AChEIs), play an important role in smoking behavior and cognition. This pilot feasibility study tested whether an AChEI, donepezil, enhanced cognitive performance among healthy smokers.
Methods
Eighteen non-treatment seeking daily smokers (6 female) received either donepezil (5mg q.d) or placebo (double-blind; 2:1 allocation ratio) for four weeks. Smoking rate, side effects, and neurocognitive measures of working memory (Letter-N-back) and sustained attention (Penn Continuous Performance Task) were assessed weekly.
Results
For the working memory task, there was a significant group × load × time interaction (p=0.03) indicating that the donepezil group demonstrated an increase in true positives from baseline to week 4 at the highest working memory load (3-back). The placebo group showed no change in accuracy. For the sustained attention task, there was a marginal effect in the same direction for discriminability, or d', p=0.08. There were no significant effects on reaction time during either task. There was also a reduction in cigarettes per day in the placebo group, but not the donepezil group.
Conclusions
AChEIs, such as donepezil, may have pro-cognitive effects among healthy smokers while they continue to smoke as usual. Given the association between cognitive deficits and relapse, AChEIs should be explored as potential therapeutics for smoking cessation.
doi:10.1016/j.drugalcdep.2012.04.019
PMCID: PMC3424358  PMID: 22595038
smoking; nicotine; acetylcholine; cognition; cognitive enhancers; working memory
3.  Nicotine Dependence Pharmacogenetics: Role of Genetic Variation in Nicotine-Metabolizing Enzymes 
Journal of neurogenetics  2009;23(3):252-261.
Nicotine-dependence pharmacogenetics research is an emerging field, and a number of studies have begun to characterize the clinical relevance and predictive power of genetic variation in drug-metabolizing enzymes and drug target genes for response to medication. The present paper focuses on evidence for the role of nicotine-metabolizing enzymes in smoking behavior and response to treatment. Nicotine metabolism is mediated primarily by cytochrome P450 2A6 (CYP2A6). Genetic variation in the CYP2A6 gene has been linked with several smoking behavior phenotypes. Individuals who carry null or reduced activity alleles for CYP2A6 smoke fewer cigarettes per day, are less dependent on nicotine, and may have an easier time quitting smoking. A phenotypic measure of CYP2A6 enzyme activity, defined as the ratio of the nicotine metabolites 3′hydroxycotinine/cotinine, also predicts successful quitting with the transdermal nicotine patch, and counseling alone. Faster metabolizers of nicotine respond more poorly to these treatments; however, they may be excellent candidates for non-nicotine therapies, such as bupropion. Inherited variation in the CYP2B6 enzyme is also associated with response to bupropion treatment and counseling alone for smoking cessation. Inhibition of the CYP2A6 enzyme to slow nicotine metabolism is a promising approach to increase nicotine availability and potentially reduce harm from tobacco smoking.
doi:10.1080/01677060802572887
PMCID: PMC3772540  PMID: 19169923
tobacco; nicotine; addiction; genetics; pharmacogenetics
4.  DRD1 Associations with Smoking Abstinence Across Slow and Normal Nicotine Metabolizers 
Pharmacogenetics and Genomics  2012;22(7):551-554.
Nicotine metabolism and genetic variation have an impact on nicotine addiction and smoking abstinence, but further research is required. The nicotine metabolite ratio (NMR) is a robust biomarker of nicotine metabolism used to categorize slow and normal nicotine metabolizers (lower 25th quartile cutoff). In two randomized clinical trials of smoking abstinence treatments, we conducted NMR-stratified analyses on smoking abstinence across 13 regions coding for nicotinic acetylcholine receptors and proteins involved in the dopamine reward system. Gene × NMR interaction P-values were adjusted for multiple correlated tests, and we used a Bonferroni-corrected α-level of 0.004 to determine system-wide significance. Three SNPs in DRD1 (rs11746641, rs2168631, rs11749035) had significant interactions (0.001 ≤ adjusted P-values ≤ 0.004), with increased odds of abstinence within slow metabolizers (ORs=3.1–3.5, 95% CI 1.7–6.7). Our findings support the role of DRD1 in nicotine dependence, and identify genetic and nicotine metabolism profiles that may interact to impact nicotine dependence.
doi:10.1097/FPC.0b013e3283539062
PMCID: PMC3376177  PMID: 22495174
Genetic association studies; heterogeneity; smoking abstinence; nicotine metabolism; nicotine metabolite ratio; DRD1
5.  µ-opioid Receptor Availability in the Amygdala is Associated with Smoking for Negative Affect Relief 
Psychopharmacology  2012;222(4):701-708.
Rationale
The perception that smoking relieves negative affect contributes to smoking persistence. Endogenous opioid neurotransmission, and the µ-opioid receptor (MOR) in particular, plays a role in affective regulation and is modulated by nicotine.
Objectives
We examined the relationship of µ-opioid receptor binding availability in the amygdala to the motivation to smoke for negative affect relief and to the acute effects of smoking on affective responses.
Methods
Twenty-two smokers were scanned on two separate occasions after overnight abstinence using [11C]carfentanil positron emission tomography imaging: after smoking a nicotine-containing cigarette and after smoking a denicotinized cigarette. Self-reports of smoking motives were collected at baseline, and measures of positive and negative affect were collected pre- and post- cigarette smoking.
Results
Higher MOR availability in the amygdala was associated with motivation to smoke to relieve negative affect. However, MOR availability was unrelated to changes in affect after smoking either cigarette.
Conclusions
Increased MOR availability in amygdala may underlie the motivation to smoke for negative affective relief. These results are consistent with previous data highlighting the role of µ-opioid receptor neurotransmission in smoking behavior.
doi:10.1007/s00213-012-2673-5
PMCID: PMC3670416  PMID: 22389047
Smoking motivation; µ-opioid receptor; amygdala; affect regulation
6.  Association of the Nicotine Metabolite Ratio and CHRNA5/CHRNA3 Polymorphisms With Smoking Rate Among Treatment-Seeking Smokers 
Nicotine & Tobacco Research  2011;13(6):498-503.
Introduction:
Genome-wide association studies have linked single-nucleotide polymorphisms (SNPs) in the CHRNA5/A3/B4 gene cluster with heaviness of smoking. The nicotine metabolite ratio (NMR), a measure of the rate of nicotine metabolism, is associated with the number of cigarettes per day (CPD) and likelihood of cessation. We tested the potential interacting effects of these two risk factors on CPD.
Methods:
Pretreatment data from three prior clinical trials were pooled for analysis. One thousand and thirty treatment seekers of European ancestry with genotype data for the CHRNA5/A3/B4 SNPs rs578776 and rs1051730 and complete data for NMR and CPD at pretreatment were included. Data for the third SNP, rs16969968, were available for 677 individuals. Linear regression models estimated the main and interacting effects of genotype and NMR on CPD.
Results:
We confirmed independent associations between the NMR and CPD as well as between the SNPs rs16969968 and rs1051730 and CPD. We did not detect a significant interaction between NMR and any of the SNPs examined.
Conclusions:
This study demonstrates the additive and independent association of the NMR and SNPs in the CHRNA5/A3/B4 gene cluster with smoking rate in treatment-seeking smokers.
doi:10.1093/ntr/ntr012
PMCID: PMC3103715  PMID: 21385908
7.  Convergent Evidence that Choline Acetyltransferase Gene Variation is Associated with Prospective Smoking Cessation and Nicotine Dependence 
Neuropsychopharmacology  2010;35(6):1374-1382.
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.
doi:10.1038/npp.2010.7
PMCID: PMC2855736  PMID: 20147892
nicotine; smoking cessation; choline acetyltransferase ChAT; pharmacogenetics; addiction; Pharmacogenetics/Pharmacogenomics; Addiction & Substance Abuse; Clinical Pharmacology/Trials; Psychiatry & Behavioral Sciences; Nicotine; Smoking Cessation; choline acetyltransferase ChAT
8.  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 following eight weeks of transdermal nicotine therapy for smoking cessation. The genotyping panel included 169 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 pre-treatment 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 utilized 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.
doi:10.1038/npp.2010.7
PMCID: PMC2855736  PMID: 20147892
nicotine; smoking cessation; choline acetyltransferase ChAT; pharmacogenetics; addiction
9.  Neuroimaging, Genetics and the Treatment of Nicotine Addiction 
Behavioural brain research  2008;193(2):159-169.
Advances in neuroimaging and genomics provide an unprecedented opportunity to accelerate medication development for nicotine dependence and other addictions. Neuroimaging studies have begun to elucidate the functional neuroanatomy and neurochemistry underlying effects of nicotine and nicotine abstinence. In parallel, genetic studies, including both candidate gene and genome-wide association approaches, are identifying key neurobiological targets and pathways important in addiction to nicotine. To date, only a few neuroimaging studies have explored effects of nicotine or abstinence on brain activity as a function of genotype. Most analyses of genotype are retrospective, resulting in small sample sizes for testing effects of the minor alleles for candidate genes. The purpose of this review is to provide an outline of the work in neuroimaging, genetics, and nicotine dependence, and to explore the potential for increased integration of these approaches to improve nicotine dependence treatment.
doi:10.1016/j.bbr.2008.05.021
PMCID: PMC2600518  PMID: 18599130
Neuroimaging; Genetics; Nicotine; Smoking; Pharmacogenetics; fMRI; PET
10.  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; Kass and Raftery 1995), 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.
doi:10.1002/ajmg.b.30669
PMCID: PMC2655206  PMID: 18165968
Bayes factor; Bayesian hypothesis test; bupropion; importance sampling; pharmacogenomics; single-nucleotide polymorphism
11.  Nicotine Abstinence-induced Cerebral Blood Flow Changes by Genotype 
Neuroscience letters  2008;438(3):275-280.
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 >12 hours abstinence vs. satiety) [24], and were genotyped for variants in the dopamine D2 receptor (DRD2-141 Ins/DelC; DRD2 C957T); a dopamine metabolizing enzyme (COMT val/val), 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.
doi:10.1016/j.neulet.2008.04.084
PMCID: PMC2474789  PMID: 18499348
perfusion MRI; nicotine; addiction; genetics

Results 1-11 (11)