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

Biol Psychiatry. 2013 Oct 1;74(7):538-46. doi: 10.1016/j.biopsych.2013.01.035. Epub 2013 Mar 15.


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: NCT00830739.

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

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Amygdala / drug effects*
  • Amygdala / physiology*
  • Benzazepines / administration & dosage
  • Benzazepines / pharmacology*
  • Brain Mapping
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / physiology*
  • Double-Blind Method
  • Down-Regulation
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Nicotine / administration & dosage
  • Nicotine / pharmacology*
  • Nicotinic Agonists / pharmacology*
  • Quinoxalines / administration & dosage
  • Quinoxalines / pharmacology*
  • Rest
  • Smoking Cessation*
  • Varenicline
  • Young Adult


  • Benzazepines
  • Nicotinic Agonists
  • Quinoxalines
  • Nicotine
  • Varenicline

Associated data