Down-Regulation of Amygdala and Insula Functional Circuits by Varenicline and Nicotine in Abstinent Cigarette Smokers

doi:10.1016/j.biopsych.2013.01.035

Biological Psychiatry

Volume 74, Issue 7, 1 October 2013, Pages 538-546

https://doi.org/10.1016/j.biopsych.2013.01.035 Get rights and content

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.

Section snippets

Participants

Cigarette smokers (n = 24; 12 female subjects) and nonsmokers (n = 20; 10 female subjects) completed identical procedures. Participants were right-handed, 18 to 55 years of age, and reported no history of drug dependence (other than nicotine in smokers), neurological or psychiatric disorders, or contraindications for magnetic resonance imaging scanning. Smokers were 36±10 years of age (mean±SD), reported daily cigarette use for 18±11 years, smoked 18±8 cigarettes per day, and were moderately

Amygdala-Centric rsFC: Smoker Drug Effects

The left and right amygdala seeds identified ICNs that included bilateral amygdala and hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsomedial prefrontal cortex (dmPFC) (Figure S2 in Supplement 1) consistent with previous reports 9, 22. We subsequently performed whole-brain pill×patch analyses to identify regions whose rsFC with the amygdala was modulated by drugs in abstinent smokers. Focusing on the left seed, this analysis identified drug-induced rsFC modulations between the

Discussion

We examined the impact of varenicline and nicotine (administered both alone and in combination) on amygdala and insula circuit dynamics and provide the first empirical support for varenicline’s dual (partial agonist/antagonist) action profile in the human brain. While this dual mechanism of action may explain varenicline’s greater relative efficacy over other pharmacotherapies 41, 54, supporting neurobiological evidence has to date come only from cellular and preclinical data (42). Beginning

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Archival ReportDown-Regulation of Amygdala and Insula Functional Circuits by Varenicline and Nicotine in Abstinent Cigarette Smokers

Background

Methods

Results

Conclusions

Section snippets

Participants

Amygdala-Centric rsFC: Smoker Drug Effects

Discussion

Clin Psychol Rev

Brain Res

Trends Neurosci

Brain Res Rev

Neuroimage

Pharmacol Biochem Behav

Neurosci Biobehav Rev

Biol Psychiatry

Neuroimage

Neuroimage

Neuroimage

Neuroimage

Trends Cogn Sci

Neuroimage

Biol Psychiatry

Neuropharmacology

Trends Pharmacol Sci

Biol Psychiatry

Biochem Pharmacol

Neuroimage

Neuroimage

Neuroimage

Neuroimage

Neurosci Biobehav Rev

Biol Psychiatry

Biol Psychiatry

Neuroimage

Neurosci Biobehav Rev

Neuroimage

Neuroimage

Effects of abstinence from tobacco: Valid symptoms and time course

Nicotine Tob Res

Altered amygdala function in nicotine addiction: Insights from human neuroimaging studies

Neuropsychologia

Damage to the insula disrupts addiction to cigarette smoking

Science

Archival Report
Down-Regulation of Amygdala and Insula Functional Circuits by Varenicline and Nicotine in Abstinent Cigarette Smokers