ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2020
(2R,6R)-hydroxynorketamine rapidly potentiates hippocampal glutamatergic transmission through a synapse-specific presynaptic mechanism.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 66 citations in OpenAlex.
- A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers.Clinical pharmacology and therapeutics · 2024Trial
- Sex-dependent metabolism of ketamine and (Journal of psychopharmacology (Oxford, England) · 2022Trial
- Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2020Trial
- From depression to bone health: examining the skeletal effects of classical and rapid-acting antidepressants.The international journal of neuropsychopharmacology · 2026Review
- The effects of low-dose ketamine and (2R,6R)-Hydroxynorketamine on affective behaviors associated with protracted oxycodone withdrawal.Psychopharmacology · 2026Article
- Somatostatin-expressing neurons in the zona incerta regulate chronic stress response and modulate depression-like behaviors.Molecular psychiatry · 2026Article
- A Time-Sensitive Plasticity Distinguishes the Rapid and Sustained Synaptic Actions of Ketamine from Its (2The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Prefrontal contribution to passive coping behaviour in chronic stress and treatment by fast-acting antidepressant.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Review
- Use of Single Prolonged Stress to Model Post-traumatic Stress Disorder in Rodents: What We Found and Where to Next?Current neuropharmacology · 2026Review
- Review
- Mechanism of antidepressant action of ketamine and differences between its two enantiomers.Journal of anesthesia and translational medicine · 2025Review
- Bioactive ketamine metabolite exerts in vivo neuroplastogenic effects to improve hippocampal function in a treatment-resistant depression model.Cell reports · 2025Article
- Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Targeting metaplasticity mechanisms to promote sustained antidepressant actions.Molecular psychiatry · 2024Review
- cAMP-dependent protein kinase signaling is required for (Journal of neurophysiology · 2024Article
- Pharmacological Mechanism of Ketamine in Suicidal Behavior Based on Animal Models of Aggressiveness and Impulsivity: A Narrative Review.Pharmaceuticals (Basel, Switzerland) · 2023Review
- NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- (2R,6R)-Hydroxynorketamine Treatment of Rats Exposed to Repetitive Low-Level Blast Injury.Neurotrauma reports · 2023Article
- (2R,6R)-hydroxynorketamine acts through GluA1-induced synaptic plasticity to alleviate PTSD-like effects in rat models.Neurobiology of stress · 2022Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.