期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：1
页码：297-302
DOI：10.1073/pnas.1814709116
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Ketamine, a noncompetitive N -methyl-d -aspartate (NMDA) receptor antagonist, produces rapid and long-lasting antidepressant effects in major depressive disorder (MDD) patients. (2 R ,6 R )-Hydroxynorketamine [(2 R ,6 R )-HNK], a metabolite of ketamine, is reported to produce rapid antidepressant effects in rodent models without the side effects of ketamine. Importantly, (2 R ,6 R )-HNK does not block NMDA receptors like ketamine, and the molecular signaling mechanisms for (2 R ,6 R )-HNK remain unknown. Here, we examined the involvement of BDNF/TrkB/mechanistic target of rapamycin complex 1 (mTORC1) signaling in the antidepressant actions of (2 R ,6 R )-HNK. Intramedial prefrontal cortex (intra-mPFC) infusion or systemic (2 R ,6 R )-HNK administration induces rapid and long-lasting antidepressant effects in behavioral tests, identifying the mPFC as a key region for the actions of (2 R ,6 R )-HNK. The antidepressant actions of (2 R ,6 R )-HNK are blocked in mice with a knockin of the BDNF Val66Met allele (which blocks the processing and activity-dependent release of BDNF) or by intra-mPFC microinjection of an anti-BDNF neutralizing antibody. Blockade of L-type voltage-dependent Ca2+ channels (VDCCs), required for activity-dependent BDNF release, also blocks the actions of (2 R ,6 R )-HNK. Intra-mPFC infusion of pharmacological inhibitors of TrkB or mTORC1 signaling, which are downstream of BDNF, also block the actions of (2 R ,6 R )-HNK. Moreover, (2 R ,6 R )-HNK increases synaptic function in the mPFC. These findings indicate that activity-dependent BDNF release and downstream TrkB and mTORC1 signaling, which increase synaptic function in the mPFC, are required for the rapid and long-lasting antidepressant effects of (2 R ,6 R )-HNK, supporting the potential use of this metabolite for the treatment of MDD.
关键词：BDNF ; depression ; mTORC1 ; ketamine ; (2 R ,6 R )-hydroxynorketamine
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