McLean Hospital, Belmont, MA, 02478, USA.
Harvard Medical School, Boston, MA, USA.
Neuropsychopharmacology. 2018 Nov;43(12):2445-2451. doi: 10.1038/s41386-018-0069-x. Epub 2018 Apr 19.
Nicotine dependence and major depressive disorder (MDD) are highly comorbid, yet causal links between these prevalent disorders are unclear. One possible mechanism is that nicotine ameliorates MDD-related neurobiological dysfunction in specific networks. For instance, cortico-striatal circuitry is enhanced by nicotine, and such paths are disrupted in individuals with MDD. Specifically, MDD has been associated with reduced connectivity between the nucleus accumbens (NAc) and rostral anterior cingulate cortex (rACC) but enhanced connectivity between the dorsal striatum (DS) and dorsolateral prefrontal cortex (DLPFC). Determining whether nicotine normalizes these circuits in non-smokers with MDD may elucidate mechanisms underlying links between disorders. This was tested by administering placebo and a 2-mg dose of nicotine to unmedicated non-smokers with and without MDD prior to collecting resting-state functional magnetic imaging data using a cross-over design. On placebo, individuals with MDD showed significantly reduced NAc-rACC and a trend for enhanced DS-DLPFC functional connectivity relative to healthy controls. In MDD, acute nicotine administration normalized both pathways to the level of healthy controls, while having no impact on healthy controls. Nicotine's effects on NAc-rACC connectivity was influenced by anhedonia, consistent with the role of this network in reward and nicotine's ability to enhance reward deficiencies in MDD. These results indicate that nicotine normalizes dysfunctional cortico-striatal communication in unmedicated non-smokers with MDD. Nicotine's influence on these circuitries highlights a possible mechanism whereby individuals with MDD are more vulnerable to develop nicotine dependence. Findings suggest that nicotinic agents may have therapeutic effects on disrupted cortico-striatal connectivity.
尼古丁依赖和重度抑郁症（MDD）高度共病，但这些常见疾病之间的因果关系尚不清楚。一种可能的机制是，尼古丁改善了特定网络中与 MDD 相关的神经生物学功能障碍。例如，尼古丁增强了皮质纹状体回路，而 MDD 患者的这种路径被破坏。具体来说，MDD 与伏隔核（NAc）和额前扣带皮层（rACC）之间的连通性降低有关，但背侧纹状体（DS）和背外侧前额叶皮层（DLPFC）之间的连通性增强。确定尼古丁是否能使 MDD 非吸烟者的这些回路正常化，可能阐明疾病之间联系的机制。这是通过交叉设计，在非吸烟的 MDD 患者和非 MDD 患者中给予安慰剂和 2 毫克尼古丁剂量，然后在采集静息状态功能磁共振成像数据之前进行测试的。在安慰剂组中，与健康对照组相比，MDD 患者的 NAc-rACC 和 DS-DLPFC 功能连通性均显著降低，呈趋势性增强。在 MDD 中，急性尼古丁给药使两条通路均正常化至健康对照组的水平，而对健康对照组没有影响。尼古丁对 NAc-rACC 连通性的影响受快感缺失的影响，这与该网络在奖励中的作用以及尼古丁增强 MDD 中奖励缺陷的能力一致。这些结果表明，尼古丁使未用药的 MDD 非吸烟者的皮质纹状体功能障碍沟通正常化。尼古丁对这些回路的影响突出了一种机制，即 MDD 患者更容易发展为尼古丁依赖。研究结果表明，尼古丁类药物可能对皮质纹状体连通性中断具有治疗作用。
