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Down-regulation of amygdala and insula functional circuits by varenicline and nicotine in abstinent cigarette smokers.

ABSTRACT: BACKGROUND:Although the amygdala and insula are regarded as critical neural substrates perpetuating cigarette smoking, little is known about their circuit-level interactions with interconnected regions during nicotine withdrawal or following pharmacotherapy administration. To elucidate neurocircuitry associated with early smoking abstinence, we examined the impact of varenicline and nicotine, two modestly efficacious pharmacologic cessation aids, on amygdala- and insula-centered circuits using resting-state functional connectivity (rsFC). METHODS:In a functional magnetic resonance imaging study employing a two-drug, placebo-controlled design, 24 overnight-abstinent smokers and 20 nonsmokers underwent ?17 days of varenicline and placebo pill administration and were scanned, on different days under each condition, wearing a transdermal nicotine or placebo patch. We examined the impact of varenicline and nicotine (both alone and in combination) on amygdala- and insula-centered rsFC using seed-based assessments. RESULTS:Beginning with a functionally defined amygdala seed, we observed that rsFC strength in an amygdala-insula circuit was down-regulated by varenicline and nicotine in abstinent smokers. Using this identified insula region as a new seed, both drugs similarly decreased rsFC between the insula and constituents of the canonical default-mode network (posterior cingulate cortex, ventromedial/dorsomedial prefrontal cortex, parahippocampus). Drug-induced rsFC modulations were critically linked with nicotine withdrawal, as similar effects were not detected in nonsmokers. CONCLUSIONS:These results suggest that nicotine withdrawal is associated with elevated amygdala-insula and insula-default-mode network interactions. As these potentiated interactions were down-regulated by two pharmacotherapies, this effect may be a characteristic shared by pharmacologic agents promoting smoking cessation. Decreased rsFC in these circuits may contribute to amelioration of subjective withdrawal symptoms.

SUBMITTER: Sutherland MT

PROVIDER: S-EPMC3775982 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Down-regulation of amygdala and insula functional circuits by varenicline and nicotine in abstinent cigarette smokers.

Sutherland Matthew T MT Carroll Allison J AJ Salmeron Betty Jo BJ Ross Thomas J TJ Hong L Elliot LE Stein Elliot A EA

Biological psychiatry 20130315 7

<h4>Background</h4>Although the amygdala and insula are regarded as critical neural substrates perpetuating cigarette smoking, little is known about their circuit-level interactions with interconnected regions during nicotine withdrawal or following pharmacotherapy administration. To elucidate neurocircuitry associated with early smoking abstinence, we examined the impact of varenicline and nicotine, two modestly efficacious pharmacologic cessation aids, on amygdala- and insula-centered circuits ...[more]

PMID: 23506999

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Project description:Attenuated activity in performance-monitoring brain regions following erroneous actions may contribute to the repetition of maladaptive behaviors such as continued drug use. Externalizing is a broad personality construct characterized by deficient impulse control, vulnerability to addiction and reduced neurobiological indices of error processing. The insula and dorsal anterior cingulate cortex (dACC) are regions critically linked with error processing as well as the perpetuation of cigarette smoking. As such, we examined the interrelations between externalizing tendencies, erroneous task performance, and error-related insula and dACC activity in overnight-deprived smokers (n?=?24) and non-smokers (n?=?20). Participants completed a self-report measure assessing externalizing tendencies (Externalizing Spectrum Inventory) and a speeded Flanker task during functional magnetic resonance imaging scanning. We observed that higher externalizing tendencies correlated with the occurrence of more performance errors among smokers but not non-smokers. Suggesting a neurobiological contribution to such suboptimal performance among smokers, higher externalizing also predicted less recruitment of the right insula and dACC following error commission. Critically, this error-related activity fully mediated the relationship between externalizing traits and error rates. That is, higher externalizing scores predicted less error-related right insula and dACC activity and, in turn, less error-related activity predicted more errors. Relating such regional activity with a clinically relevant construct, less error-related right insula and dACC responses correlated with higher tobacco craving during abstinence. Given that inadequate error-related neuronal responses may contribute to continued drug use despite negative consequences, these results suggest that externalizing tendencies and/or compromised error processing among subsets of smokers may be relevant factors for smoking cessation success.

Project description:Hyperactive amygdala functioning may underlie emotional dysregulation during smoking abstinence and represents one neurobiological target for pharmacological cessation aids. Available pharmacotherapies (e.g., nicotine replacement and varenicline) aid only a subset of individuals with smoking cessation and therefore elucidating the neurobiological impact of these medications is critical to expedite improved interventions. In a fMRI study employing a within-subject, double-blind, placebo-controlled design, we assessed task performance and amygdala functioning during an emotional face matching paradigm following administration of nicotine and varenicline to 24 abstinent smokers and 20 nonsmokers. All participants underwent ~17days of varenicline and placebo pill administration and were scanned, on different days under each condition, wearing a transdermal nicotine or placebo patch. During the amygdala reactivity paradigm, nicotinic acetylcholine receptor (nAChR) stimulation by nicotine and varenicline decreased reaction time (RT) in abstinent smokers but not in nonsmokers. When considering all smokers as a single homogenous group, no drug-induced effects on amygdala reactivity were detected. However, in an exploratory analysis we parsed participants into subgroups according to individual differences in the propensity to demonstrate stable performance augmentation following nAChR stimulation (stable RT-improvers [SI] vs. variable RT-improvers [VI]). Using this exploratory approach, drugs appeared to modulate amygdala reactivity in only one smoker subgroup but not in either nonsmoker subgroup. Specifically, in the SI-smoker cohort abstinence-induced elevated amygdala reactivity was down-regulated by nAChR stimulation. In contrast, varenicline and nicotine did not modulate amygdala functioning in the VI-smoker cohort who displayed moderate levels of amygdala reactivity in the absence of drug administration. These results suggest that pharmacotherapies most robustly dampened amygdala functioning in smokers appearing susceptible to abstinence-induced effects. Such findings provide a step towards fractionating the smoker phenotype by discrete neurobiological characteristics.

Project description:IntroductionVarenicline is the most efficacious smoking cessation treatment; however, long-term cessation rates tend to be <25%. Nausea, the most common side effect of varenicline, observed in ~28% of individuals treated, peaks early following treatment initiation and reduces cessation success. Genetic variation influences treatment response, however genetic contributors to individual differences in side effects are less understood.MethodsWe conducted a genome-wide association study of nausea incidence at 1 week following the initiation of varenicline treatment (corresponding to the target quit date) in 189 cigarette smokers of European ancestry (NCT01314001). Additive genetic models examining the likelihood of experiencing any versus no nausea controlled for population substructure, age, and sex. Variants with minor allele frequencies (MAF)≥10% were considered.ResultsFifty-seven (30.2%) out of 189 participants reported nausea. The top variant associated with nausea was rs1568209 (odds ratio [OR] = 2.61 for A vs. G allele; 95% confidence interval [CI] = 1.65,4.15; p = 2.1e-7; MAF = 48.7%), mapping to the SLCO3A1 drug transporter gene on chromosome 15. In the same trial, rs1568209 was not associated with nausea in either the nicotine patch (p = .56; n = 181) or placebo (p = .59; n = 174) arms. In varenicline-treated smokers, the incidence of nausea was higher in females (44.6%; n = 74) versus males (20.9%; n = 115) (p = .001), however there was no evidence of a difference in the influence of rs1568209 on nausea between the sexes (p for sex*genotype interaction = .36). Future studies in larger samples are required to test the robustness of this finding.ConclusionsVariation in SLCO3A1 may influence the risk for developing nausea in varenicline-treated smokers, which may alter adherence and cessation.ImplicationsVarenicline-associated nausea reduces adherence and limits cessation success. Previous candidate gene association studies showed genetic factors influence nausea on varenicline. This pilot genome-wide investigation of nausea, the most common side effect associated with varenicline treatment and an important cause of treatment discontinuation, suggests the potential involvement of common variation in the SLCO3A1 drug transporter gene.

Project description:ImportanceQuitting smoking is enhanced by the use of pharmacotherapies, but concerns have been raised regarding the cardiovascular safety of such medications.ObjectiveTo compare the relative cardiovascular safety risk of smoking cessation treatments.Design, setting, and participantsA double-blind, randomized, triple-dummy, placebo- and active-controlled trial (Evaluating Adverse Events in a Global Smoking Cessation Study [EAGLES]) and its nontreatment extension trial was conducted at 140 multinational centers. Smokers, with or without established psychiatric diagnoses, who received at least 1 dose of study medication (n = 8058), as well as a subset of those who completed 12 weeks of treatment plus 12 weeks of follow up and agreed to be followed up for an additional 28 weeks (n = 4595), were included.InterventionsVarenicline, 1 mg twice daily; bupropion hydrochloride, 150 mg twice daily; and nicotine replacement therapy, 21-mg/d patch with tapering.Main outcomes and measuresThe primary end point was the time to development of a major adverse cardiovascular event (MACE: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) during treatment; secondary end points were the occurrence of MACE and other pertinent cardiovascular events (MACE+: MACE or new-onset or worsening peripheral vascular disease requiring intervention, coronary revascularization, or hospitalization for unstable angina).ResultsOf the 8058 participants, 3553 (44.1%) were male (mean [SD] age, 46.5 [12.3] years). The incidence of cardiovascular events during treatment and follow-up was low (<0.5% for MACE; <0.8% for MACE+) and did not differ significantly by treatment. No significant treatment differences were observed in time to cardiovascular events, blood pressure, or heart rate. There was no significant difference in time to onset of MACE for either varenicline or bupropion treatment vs placebo (varenicline: hazard ratio, 0.29; 95% CI, 0.05-1.68 and bupropion: hazard ratio, 0.50; 95% CI, 0.10-2.50).Conclusions and relevanceNo evidence that the use of smoking cessation pharmacotherapies increased the risk of serious cardiovascular adverse events during or after treatment was observed. The findings of EAGLES and its extension trial provide further evidence that smoking cessation medications do not increase the risk of serious cardiovascular events in the general population of smokers.Trial registrationclinicaltrials.gov Identifier: NCT01574703.

Project description:A few studies have assessed the short-term effects of low-dose nicotine e-cigarettes, while data about nicotine-free e-cigarettes (NF e-cigarettes) are scanty. Concerns have been expressed about the use of NF e-cigarettes, because of the high concentrations of propylene glycol and other compounds in the e-cigarette vapor.This laboratory-based study was aimed to compare the effects of ad libitum use of a NF e-cigarette or and a traditional cigarette for 5 min in healthy adult smokers (n = 10) and non-smokers (n = 10). The main outcome measures were pulmonary function tests, fraction of exhaled nitric oxide (FeNO) and fractional concentration of carbon monoxide (FeCO) in exhaled breath.The traditional cigarette induced statistically significant increases in FeCO in both smokers and non-smokers, while no significant changes were observed in FeNO. In non-smokers, the traditional cigarette induced a significant decrease from baseline in FEF75 (81 % ± 35 % vs 70.2 % ± 28.2 %, P = 0.013), while in smokers significant decreases were observed in FEF25 (101.3 % ± 16.4 % vs 93.5 % ± 31.7 %, P = 0.037), FEV1 (102.2 % ± 9.5 % vs 98.3 % ± 10 %, P = 0.037) and PEF (109.5 % ± 14.6 % vs 99.2 % ± 17.5 %, P = 0.009). In contrast, the only statistically significant effects induced by the NF e-cigarette in smokers were reductions in FEV1 (102.2 % ± 9.5 % vs 99.5 ± 7.6 %, P = 0.041) and FEF25 (103.4 % ± 16.4 % vs 94.2 % ± 16.2 %, P =? .014).The present study demonstrated that the specific brand of NF e-cigarette utilized did not induce any majoracute effects. In contrast, several studies have shown that both traditional cigarettes and nicotine-containing e-cigarettes have acute effects on lung function. Our study expands on previous observations on the effects of NF e-cigarettes, but also for the first time describes the changes induced by smoking one traditional cigarette in a group of never smokers.The short-term use of the specific brand of NF e-cigarette assessed in this study had no immediate adverse effects on non-smokers and only small effects on FEV1 and FEF25 in smokers. The long-term health effects of NF e-cigarette use are unknown but worthy of further investigations.Clinicaltrials.gov: NCT02102191.

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Down-regulation of amygdala and insula functional circuits by varenicline and nicotine in abstinent cigarette smokers.

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Down-regulation of amygdala and insula functional circuits by varenicline and nicotine in abstinent cigarette smokers.

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