Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function
Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function
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DOI：
10.1073/pnas.1816071116
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发表时间：
2019-03-12
影响因子：
11.1
通讯作者：
Gould, Todd D.
中科院分区：
文献类型：
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作者：
Lumsden, Eric W.;Troppoli, Timothy A.;Gould, Todd D.
临床前研究表明，（2 R，6 R）-羟基去甲氯胺酮（HNK）是一种公认的速效抗抑郁药候选者。虽然抑制NMDA型谷氨酸受体（NMDAR）是氯胺酮抗抑郁和副作用的一种机制，但（2 R，6 R）-HNK抑制NMDAR的效力尚未确定。我们使用多学科方法来确定（2 R，6 R）-HNK对NMDAR功能的影响。抗抑郁药相关的行为反应和（2 R，6 R）-HNK水平在海马细胞外区室进行了测量后，在小鼠全身（2 R，6 R）-HNK管理。评价了氯胺酮、（2 R，6 R）-HNK和（在某些情况下）（2S，6S）-HNK立体异构体对以下方面的影响：（i）小鼠中NMDA诱导的致死性，（ii）小鼠海马切片的CA 1场中的NMDAR介导的场兴奋性突触后电位（fEPSP），（iii）大鼠海马切片的CA 1锥体神经元中的NMDA介导的微小兴奋性突触后电流（mEPSC）和NMDA诱发的电流，和（iv）在非洲爪蟾卵母细胞中表达的重组NMDAR。虽然单次腹腔注射10 mg/kg（2 R，6 R）-HNK在小鼠中产生了抗抑郁相关的行为和细胞反应，但发现（2 R，6 R）-HNK预防NMDA诱导的致死性的ED 50为228 mg/kg，而氯胺酮为6.4 mg/kg。10 mg/kg（2 R，6 R）-HNK剂量产生的最大海马细胞外浓度与8 μ M相似，远低于体外抑制突触和突触外NMDAR所需的浓度。(2S在抑制NMDAR方面，（2 R，6S）-HNK比（2 R，6 R）-HNK更有效，但不如氯胺酮有效。这些数据证明了（2 R，6 R; 2S，6S）HNK对NMDAR抑制的立体选择性，并支持直接NMDAR抑制不会促进（2 R，6 R）-HNK的抗抑郁相关作用的结论。
Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) is a putative fast-acting antidepressant candidate. Although inhibition of NMDA-type glutamate receptors (NMDARs) is one mechanism proposed to underlie ketamine's antidepressant and adverse effects, the potency of (2R,6R)-HNK to inhibit NMDARs has not been established. We used a multidisciplinary approach to determine the effects of (2R,6R)-HNK on NMDAR function. Antidepressant-relevant behavioral responses and (2R,6R)-HNK levels in the extracellular compartment of the hippocampus were measured following systemic (2R,6R)-HNK administration in mice. The effects of ketamine, (2R,6R)-HNK, and, in some cases, the (2S,6S)-HNK stereoisomer were evaluated on the following: (i) NMDA-induced lethality in mice, (ii) NMDAR-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 field of mouse hippocampal slices, (iii) NMDAR-mediated miniature excitatory postsynaptic currents (mEPSCs) and NMDA-evoked currents in CA1 pyramidal neurons of rat hippocampal slices, and (iv) recombinant NMDARs expressed in Xenopus oocytes. While a single i.p. injection of 10 mg/kg (2R,6R)-HNK exerted antidepressant-related behavioral and cellular responses in mice, the ED50 of (2R,6R)-HNK to prevent NMDA-induced lethality was found to be 228 mg/kg, compared with 6.4 mg/kg for ketamine. The 10 mg/kg (2R,6R)-HNK dose generated maximal hippocampal extracellular concentrations of similar to 8 mu M, which were well below concentrations required to inhibit synaptic and extrasynaptic NMDARs in vitro. (2S,6S)-HNK was more potent than (2R,6R)-HNK, but less potent than ketamine at inhibiting NMDARs. These data demonstrate the stereoselectivity of NMDAR inhibition by (2R,6R; 2S,6S)HNK and support the conclusion that direct NMDAR inhibition does not contribute to antidepressant-relevant effects of (2R,6R)-HNK.