PMID- 31216563 OWN - NLM STAT- MEDLINE DCOM- 20201228 LR - 20210731 IS - 1740-634X (Electronic) IS - 0893-133X (Print) IS - 0893-133X (Linking) VI - 45 IP - 2 DP - 2020 Jan TI - (2R,6R)-hydroxynorketamine rapidly potentiates hippocampal glutamatergic transmission through a synapse-specific presynaptic mechanism. PG - 426-436 LID - 10.1038/s41386-019-0443-3 [doi] AB - 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 alpha-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. FAU - Riggs, Lace M AU - Riggs LM AUID- ORCID: 0000-0003-4368-4089 AD - Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. AD - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. FAU - Aracava, Yasco AU - Aracava Y AD - Department of Epidemiology and Public Health, Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. FAU - Zanos, Panos AU - Zanos P AD - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. FAU - Fischell, Jonathan AU - Fischell J AD - Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. FAU - Albuquerque, Edson X AU - Albuquerque EX AD - Department of Epidemiology and Public Health, Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. AD - Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. FAU - Pereira, Edna F R AU - Pereira EFR AD - Department of Epidemiology and Public Health, Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. AD - Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. FAU - Thompson, Scott M AU - Thompson SM AD - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. AD - Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. FAU - Gould, Todd D AU - Gould TD AD - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. gouldlab@me.com. AD - Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. gouldlab@me.com. AD - Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. gouldlab@me.com. AD - Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA. gouldlab@me.com. LA - eng GR - F31 MH123066/MH/NIMH NIH HHS/United States GR - T32 GM008181/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20190619 PL - England TA - Neuropsychopharmacology JT - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JID - 8904907 RN - 3KX376GY7L (Glutamic Acid) RN - 690G0D6V8H (Ketamine) RN - 81395-70-2 (6-hydroxynorketamine) SB - IM MH - Animals MH - Excitatory Postsynaptic Potentials/drug effects/physiology MH - Female MH - Glutamic Acid/*metabolism MH - Hippocampus/drug effects/*metabolism MH - Ketamine/*analogs & derivatives/pharmacology MH - Male MH - Organ Culture Techniques MH - Presynaptic Terminals/drug effects/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Synapses/drug effects/*metabolism MH - Synaptic Transmission/drug effects/*physiology PMC - PMC6901515 EDAT- 2019/06/20 06:00 MHDA- 2020/12/29 06:00 PMCR- 2021/01/01 CRDT- 2019/06/20 06:00 PHST- 2019/03/06 00:00 [received] PHST- 2019/06/11 00:00 [accepted] PHST- 2019/05/17 00:00 [revised] PHST- 2019/06/20 06:00 [pubmed] PHST- 2020/12/29 06:00 [medline] PHST- 2019/06/20 06:00 [entrez] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.1038/s41386-019-0443-3 [pii] AID - 443 [pii] AID - 10.1038/s41386-019-0443-3 [doi] PST - ppublish SO - Neuropsychopharmacology. 2020 Jan;45(2):426-436. doi: 10.1038/s41386-019-0443-3. Epub 2019 Jun 19.