BDNF Release Is Required for the Behavioral Actions of Ketamine
BDNF Release Is Required for the Behavioral Actions of Ketamine
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DOI：
10.1093/ijnp/pyu033
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发表时间：
2015-01-01
影响因子：
4.8
通讯作者：
Duman, Ronald S.
中科院分区：
文献类型：
--
作者：
Lepack, Ashley E.;Fuchikami, Manabu;Duman, Ronald S.
背景：最近的研究表明，快速抗抑郁药氯胺酮可增加内侧前额皮质 (mPFC) 的棘数量和功能，并且这些作用依赖于谷氨酸 α-氨基-3-羟基-5-甲基异恶唑-4-丙酸 (AMPA) 受体和脑源性神经营养因子 (BDNF) 的激活。体外研究还表明，AMPA 受体的激活通过激活 L 型电压依赖性钙通道 (VDCC) 来刺激 BNDF 释放。方法：基于这一证据，我们研究了 BDNF 释放的作用以及 L 型 VDCC 对氯胺酮行为行为的影响。结果：结果表明，在强迫游泳测试 (FST) 中，将中和 BDNF 抗体输注到 mPFC 中可阻断氯胺酮的行为影响。此外，我们还发现，用硝苯地平或维拉帕米这两种结构不同的 L 型钙通道拮抗剂进行预处理，可以阻断氯胺酮在 FST 中的行为效应。最后，我们表明氯胺酮治疗会刺激初级皮质神经元中的 BDNF 释放，并且这种作用可以通过抑制 AMPA 受体或 L 型 VDCC 来阻断。结论：综上所述，这些结果表明氯胺酮的抗抑郁作用是通过激活 L 型 VDCC 和释放 BDNF 介导的。他们进一步阐明了这种新型速效抗抑郁药的细胞机制。
Background: Recent studies demonstrate that the rapid antidepressant ketamine increases spine number and function in the medial prefrontal cortex (mPFC), and that these effects are dependent on activation of glutamate alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and brain-derived neurotrophic factor (BDNF). In vitro studies also show that activation of AMPA receptors stimulates BNDF release via activation of L-type voltage-dependent calcium channels (VDCC).Methods: Based on this evidence, we examined the role of BDNF release and the impact of L-type VDCCs on the behavioral actions of ketamine.Results: The results demonstrate that infusion of a neutralizing BDNF antibody into the mPFC blocks the behavioral effects of ketamine in the forced swim test (FST). In addition, we show that pretreatment with nifedipine or verapamil, two structurally-different L-type calcium channel antagonists, blocks the behavioral effects of ketamine in the FST. Finally, we show that ketamine treatment stimulates BDNF release in primary cortical neurons and that this effect is blocked by inhibition of AMPA receptors or L-type VDCCs.Conclusions: Taken together, these results indicate that the antidepressant effects of ketamine are mediated by activation of L-type VDCCs and the release of BDNF. They further elucidate the cellular mechanisms underlying this novel rapid-acting antidepressant.