Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut.
Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut.
Biol Psychiatry. 2018 Jan 1;83(1):29-37. doi: 10.1016/j.biopsych.2017.06.017. Epub 2017 Jun 23.
Brain-derived neurotrophic factor (BDNF) plays a key role in the pathophysiology and treatment of depression. Recent clinical studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in patients with depression. Rodent studies demonstrate that scopolamine increases glutamate transmission and synaptogenesis in the medial prefrontal cortex (mPFC). Here we tested the hypothesis that activity-dependent BDNF release within the mPFC is necessary for the antidepressant actions of scopolamine.
Behavioral effects of scopolamine were assessed in BDNF Val/Met knock-in mice, in which BDNF processing and release are impaired. In addition, intra-mPFC infusion of a BDNF-neutralizing antibody was performed to test the necessity of BDNF release in driving scopolamine-induced behavioral responses. Further in vivo and in vitro experiments were performed to delineate BDNF-dependent mechanisms underlying the effects of scopolamine.
We found that BDNF Met/Met mice have attenuated responses to scopolamine and that anti-BDNF antibody infusions into the mPFC prevented the antidepressant-like behavioral effects of scopolamine. In vitro experiments show that scopolamine rapidly stimulates BDNF release and tropomyosin receptor kinase B-extracellular signal-regulated kinase signaling. Moreover, these effects require alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor activation and are blocked by neuronal silencing. Importantly, pretreatment with verapamil prevented scopolamine-induced behavioral responses and BDNF-tropomyosin receptor kinase B signaling, suggesting that these effects are dependent on activation of voltage-dependent calcium channels.
The results identify an essential role for activity-dependent BDNF release in the rapid antidepressant effects of scopolamine. Attenuation of responses in BDNF Met mice indicates that patients with the Met allele may be less responsive to scopolamine.
脑源性神经营养因子（BDNF）在抑郁症的病理生理学和治疗中起着关键作用。最近的临床研究表明，东莨菪碱，一种非选择性毒蕈碱乙酰胆碱受体拮抗剂，可在抑郁症患者中产生快速的抗抑郁作用。啮齿动物研究表明，东莨菪碱可增加内侧前额叶皮层（mPFC）中的谷氨酸传递和突触形成。在这里，我们测试了这样一个假设，即在 mPFC 内，依赖于活动的 BDNF 释放对于东莨菪碱的抗抑郁作用是必要的。
在 BDNF Val/Met 基因敲入小鼠中评估了东莨菪碱的行为效应，在这些小鼠中，BDNF 的加工和释放受损。此外，还进行了内侧前额叶皮层内 BDNF 中和抗体的输注，以测试 BDNF 释放驱动东莨菪碱诱导的行为反应的必要性。进一步进行了体内和体外实验，以描绘东莨菪碱作用的 BDNF 依赖机制。
我们发现，BDNF Met/Met 小鼠对东莨菪碱的反应减弱，而抗 BDNF 抗体输注到 mPFC 可防止东莨菪碱的抗抑郁样行为效应。体外实验表明，东莨菪碱可迅速刺激 BDNF 释放和原肌球蛋白受体激酶 B-细胞外信号调节激酶信号转导。此外，这些效应需要α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体的激活，并且可以通过神经元沉默来阻断。重要的是，维拉帕米预处理可防止东莨菪碱引起的行为反应和 BDNF-原肌球蛋白受体激酶 B 信号转导，表明这些效应依赖于电压依赖性钙通道的激活。
这些结果确定了活动依赖性 BDNF 释放对于东莨菪碱快速抗抑郁作用的重要作用。BDNF Met 小鼠的反应减弱表明，携带 Met 等位基因的患者对东莨菪碱的反应可能较低。
