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

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 pharmacological cessation aids, on amygdala- and insula-centered circuits using resting-state functional connectivity (rsFC). In a fMRI 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. 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 (DMN: posterior cingulate cortex, ventro/dorsomedial prefrontal cortex, parahippocampus). Drug-induced rsFC modulations were critically linked with nicotine withdrawal as similar effects were not detected in nonsmokers. These results suggest that nicotine withdrawal is associated with elevated amygdala-insula and insula-DMN interactions. As these potentiated interactions were down-regulated by two pharmacotherapies, this effect may be a characteristic shared by pharmacological agents promoting smoking cessation. Decreased rsFC in these circuits may contribute to amelioration of subjective withdrawal symptoms. (http://www.clinicaltrials.gov, ID:NCT00830739).

尽管杏仁核和脑岛被视为使吸烟持续的关键神经基质，但在尼古丁戒断期间或药物治疗后，它们与相互连接区域在回路层面的相互作用却鲜为人知。为了阐明与早期戒烟相关的神经回路，我们利用静息态功能连接（rsFC）研究了伐尼克兰和尼古丁（两种有一定疗效的药物戒烟辅助剂）对以杏仁核和脑岛为中心的回路的影响。 在一项采用双药、安慰剂对照设计的功能性磁共振成像（fMRI）研究中，24名隔夜戒烟的吸烟者和20名非吸烟者接受了约17天的伐尼克兰和安慰剂药丸给药，并在每种条件下的不同日期，佩戴透皮尼古丁或安慰剂贴片进行扫描。我们利用基于种子的评估方法研究了伐尼克兰和尼古丁（单独使用以及联合使用）对以杏仁核和脑岛为中心的rsFC的影响。 从一个功能定义的杏仁核种子区域开始，我们观察到在戒烟的吸烟者中，伐尼克兰和尼古丁下调了杏仁核 - 脑岛回路中的rsFC强度。将这个已确定的脑岛区域作为一个新的种子，两种药物同样降低了脑岛与典型默认模式网络（DMN：后扣带回皮质、腹侧/背内侧前额叶皮质、海马旁回）组成部分之间的rsFC。药物诱导的rsFC调节与尼古丁戒断密切相关，因为在非吸烟者中未检测到类似的效应。 这些结果表明，尼古丁戒断与杏仁核 - 脑岛以及脑岛 - DMN相互作用增强有关。由于这些增强的相互作用被两种药物治疗下调，这种效应可能是促进戒烟的药物所共有的特征。这些回路中rsFC的降低可能有助于缓解主观戒断症状。（http://www.clinicaltrials.gov，编号：NCT00830739）