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Neuropsychopharmacology. 2020 Jan;45(2):426-436. doi: 10.1038/s41386-019-0443-3. Epub 2019 Jun 19.

(2R,6R)-hydroxynorketamine rapidly potentiates hippocampal glutamatergic transmission through a synapse-specific presynaptic mechanism.

Author information

1
Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
2
Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
3
Department of Epidemiology and Public Health, Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
4
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
5
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
6
Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. gouldlab@me.com.
7
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. gouldlab@me.com.
8
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. gouldlab@me.com.
9
Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA. gouldlab@me.com.

Abstract

Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) retains the rapid and sustained antidepressant-like actions of ketamine, but is spared its dissociative-like properties and abuse potential. While (2R,6R)-HNK is thought to exert its antidepressant-like effects by potentiating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission, it is unknown how it exerts this effect. The acute synaptic effects of (2R,6R)-HNK were examined by recording field excitatory postsynaptic potentials (fEPSPs) and miniature excitatory postsynaptic currents (mEPSCs) in rat hippocampal slices. (2R,6R)-HNK bath application caused a rapid and persistent potentiation of AMPAR-mediated Schaffer collateral (SC)-CA1 fEPSPs in slices derived from male and female rats. The (2R,6R)-HNK-induced potentiation occurred independent of N-methyl-D-aspartate receptor (NMDAR) activity, was accompanied by a concentration-dependent decrease in paired pulse ratios, and was occluded by raising glutamate release probability. In additon, in the presence of tetrodotoxin, (2R,6R)-HNK increased the frequency, but not amplitude, of mEPSC events, confirming a presynaptic site of action that is independent of glutamatergic network disinhibition. A dual extracellular recording configuration revealed that the presynaptic effects of (2R,6R)-HNK were synapse-selective, occurring in CA1-projecting SC terminals, but not in CA1-projecting temporoammonic terminals. Overall, we found that (2R,6R)-HNK enhances excitatory synaptic transmission in the hippocampus through a concentration-dependent, NMDAR-independent, and synapse-selective increase in glutamate release probability with no direct actions on AMPAR function. These findings provide novel insight regarding (2R,6R)-HNK's acute mechanism of action, and may inform novel antidepressant drug mechanisms that could yield superior efficacy, safety, and tolerability.

PMID:
31216563
PMCID:
PMC6901515
[Available on 2021-01-01]
DOI:
10.1038/s41386-019-0443-3

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