In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 11 ( 2019-03-12), p. 5160-5169
Abstract:
Preclinical studies indicate that (2 R ,6 R )-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 (2 R ,6 R )-HNK to inhibit NMDARs has not been established. We used a multidisciplinary approach to determine the effects of (2 R ,6 R )-HNK on NMDAR function. Antidepressant-relevant behavioral responses and (2 R ,6 R )-HNK levels in the extracellular compartment of the hippocampus were measured following systemic (2 R ,6 R )-HNK administration in mice. The effects of ketamine, (2 R ,6 R )-HNK, and, in some cases, the (2 S ,6 S )-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 (2 R ,6 R )-HNK exerted antidepressant-related behavioral and cellular responses in mice, the ED 50 of (2 R ,6 R )-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 (2 R ,6 R )-HNK dose generated maximal hippocampal extracellular concentrations of ∼8 µM, which were well below concentrations required to inhibit synaptic and extrasynaptic NMDARs in vitro. (2 S ,6 S )-HNK was more potent than (2 R ,6 R )-HNK, but less potent than ketamine at inhibiting NMDARs. These data demonstrate the stereoselectivity of NMDAR inhibition by (2 R ,6 R ;2 S ,6 S )-HNK and support the conclusion that direct NMDAR inhibition does not contribute to antidepressant-relevant effects of (2 R ,6 R )-HNK.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1816071116
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2019
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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