Antidepressant-relevant concentrations of the ketamine metabolite (2
| Autor: | Eric W, Lumsden, Timothy A, Troppoli, Scott J, Myers, Panos, Zanos, Yasco, Aracava, Jan, Kehr, Jacqueline, Lovett, Sukhan, Kim, Fu-Hua, Wang, Staffan, Schmidt, Carleigh E, Jenne, Peixiong, Yuan, Patrick J, Morris, Craig J, Thomas, Carlos A, Zarate, Ruin, Moaddel, Stephen F, Traynelis, Edna F R, Pereira, Scott M, Thompson, Edson X, Albuquerque, Todd D, Gould |
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| Rok vydání: | 2019 |
| Předmět: |
Male
animal structures N-Methylaspartate Behavior Animal Pyramidal Cells Excitatory Postsynaptic Potentials Hippocampus Receptors N-Methyl-D-Aspartate Antidepressive Agents Rats Inhibitory Concentration 50 Mice Protein Subunits Xenopus laevis nervous system PNAS Plus embryonic structures Animals Ketamine |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 116(11) |
| ISSN: | 1091-6490 |
| Popis: | 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 ED(50) 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 ∼8 µM, 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. |
| Databáze: | OpenAIRE |
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