Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):4282-4287. doi: 10.1073/pnas.1707047115. Epub 2018 Apr 2.
Cigarette smoking is the leading cause of preventable disease and death in the United States, with more persons dying from nicotine addiction than any other preventable cause of death. Even though smoking cessation incurs multiple health benefits, the abstinence rate remains low with current medications. Here we show that the AMP-activated protein kinase (AMPK) pathway in the hippocampus is activated following chronic nicotine use, an effect that is rapidly reversed by nicotine withdrawal. Increasing pAMPK levels and, consequently, downstream AMPK signaling pharmacologically attenuate anxiety-like behavior following nicotine withdrawal. We show that metformin, a known AMPK activator in the periphery, reduces withdrawal symptoms through a mechanism dependent on the presence of the AMPKα subunits within the hippocampus. This study provides evidence of a direct effect of AMPK modulation on nicotine withdrawal symptoms and suggests central AMPK activation as a therapeutic target for smoking cessation.
吸烟是美国可预防疾病和死亡的主要原因，死于尼古丁成瘾的人数超过任何其他可预防的死亡原因。尽管戒烟会带来多种健康益处，但目前的药物治疗仍然难以达到较高的戒断率。在这里，我们发现慢性尼古丁使用会激活海马体中的 AMP 激活蛋白激酶（AMPK）途径，而尼古丁戒断会迅速逆转这种作用。增加 pAMPK 水平，从而增强下游 AMPK 信号，可在尼古丁戒断后减轻焦虑样行为。我们发现，二甲双胍是一种已知的外周 AMPK 激活剂，它通过一种依赖于 AMPKα 亚基在海马体中的存在的机制，减少戒断症状。这项研究提供了 AMPK 调节对尼古丁戒断症状的直接影响的证据，并表明中枢 AMPK 激活是戒烟治疗的一个潜在靶点。
