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.

Trial registration: ClinicalTrials.gov NCT00830739.

Keywords: Amygdala; insula; nicotine; resting-state functional connectivity; varenicline; withdrawal.

Copyright © 2013 Society of Biological Psychiatry. All rights reserved.

Figures

Figure 1

Schematic illustration of the idealized varenicline (PILL) x nicotine (PATCH) pharmacological interaction. Withdrawal-induced effects on the dependent variable (DV: e.g., amygdala- and insula-centric rsFC) were expected to be greatest following smoking deprivation and in the absence of drug administration (data points A and C). Administration of nicotine was then anticipated to reduce this withdrawal-induced elevation (data points B and D) yielding the full agonist effect (A vs. B, C vs. D). Similarly, administration of varenicline alone was expected to reduce the DV (data point E) thus yielding a partial agonist effect (C vs. E). Administration of varenicline in combination with nicotine (data point F) was expected to result in an attenuated nicotine-induced response, as varenicline binds to nAChRs with higher affinity than nicotine “blocking” the full agonist response and thus yielding an antagonist effect (D vs. F). These partial agonist and antagonist effects were anticipated to yield a null effect of nicotine versus placebo patch (E vs. F) in the presence of varenicline.

Figure 2

rsFC strength in amygdala- and insula-centric circuits was decreased by nicotine and varenicline in a manner consistent with varenicline’s partial agonist profile. (A) A PILL x PATCH interaction analysis identified brain regions whose rsFC with a functionally-defined left amygdala seed (S, green) was modulated by drugs. Qualitatively, during pre-pill sessions, nicotine (vs. placebo patch) administration decreased rsFC strength between the amygdala and insula (1). This nicotine-induced decrease was internally replicated under placebo pill conditions. During active pill sessions, varenicline also decreased amygdala-insula rsFC strength when administered alone (graph, grey line) and attenuated nicotine’s impact when administered in combination (graph, red line). Similar drug-induced modulations were observed in the right precentral gyrus (2) and superior parietal lobule (3); see also Fig. S3 and Table S1. (B) A PILL x PATCH interaction analysis identified brain regions whose rsFC with a left insula seed (S, green: obtained from the amygdala-centric analysis) was modulated by drugs. Both varenicline and nicotine decreased rsFC strength between the insula and PCC (1). Similar drug-induced modulations were observed in the left parahippocampus extending into amygdala (2), right parahippocampus (3), vmPFC (4), dmPFC (5), and mid-cingulate cortex (6); see also Fig. S4 and Table S3. Data are reported as mean ± SEM.

Figure 3

rsFC strength in a PCC-mPFC circuit was increased by nicotine in abstinent smokers. A whole-brain PATCH main effect identified brain regions whose rsFC with a PCC seed (S, green: center coordinate obtained from the insula-centric analysis in Fig. 2B; x = 2, y = −54, x = 26; 29 voxels) was modulated by nicotine. Across all PILL-levels, nicotine increased rsFC between the PCC and mPFC (1: x = 6, y = 60, x = 2; 56 voxels). No indications of a varenicline effect were observed.

Figure 4

rsFC strength in amygdala- and insula-centric circuits was decreased by nicotine in abstinent smokers but not in nonsmokers. (A) A GROUP x PATCH interaction analysis identified brain regions whose rsFC with a left amygdala seed (S, green: same as in Fig. 2A) showed differential responses to nicotine challenge in smokers versus nonsmokers. Qualitatively, nicotine decreased rsFC between the amygdala and insula (1) in the smoker but not the nonsmoker group. Note: This whole-brain between-group strategy independently identified similar regions as those detected in the within-smoker analysis (c.f., Fig. 2A). Similar interaction patterns were observed in the precentral gyrus (2), parietal regions (3), and posterior insula (4); see also Fig. S6 and Table S4. (B) A GROUP x PATCH interaction analysis identified brain regions whose rsFC with a left insula seed (S, green: same as in Fig. 2B) showed differential responses to nicotine challenge in smokers versus nonsmokers. Nicotine decreased rsFC between the insula and PCC/precuneus (1) in the smoker but not the nonsmoker group. Similar interaction patterns were observed in the vmPFC (2), dmPFC (3), and mid-cingulate cortex (4); see also Fig. S7 and Table S5.