Distinct synaptic mechanisms drive the behavioral response to acute stress and rapid correction by ketamine.
Ji-Woon Kim, Benjamin Kleinfelter, Ege T Kavalali, Lisa M Monteggia
Neuropsychopharmacology November 1, 2024 DOI: 10.1038/s41386-024-01908-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | physostigmine ketamine |
| Topics | Esketamine Ketamine |
| Keywords | Depression treatment Ketamine research Brain chemistry Psychopharmacology |
| Citations | 3 |
| Key findings | Ketamine rapidly restores glutamatergic synaptic efficacy in the hippocampus, countering the long-term depression of glutamate release and behavioral effects induced by physostigmine. |
Abstract
Prevailing hypotheses on the mechanisms of antidepressant action posit that antidepressants directly counteract deficiencies in major neurotransmitter signaling systems that underlie depression. The rapidly acting antidepressant ketamine has been postulated to correct excess glutamatergic signaling via glutamatergic antagonism leading to the rescue of neuronal structural deficits and reversal of behavioral symptoms. We studied this premise using systemic administration of the acetylcholinesterase inhibitor physostigmine, which has been shown to rapidly elicit a shorter-term period of depressed mood in humans via cholinergic mechanisms. We observed that physostigmine induces acute stress in tandem with long term depression of glutamate release in the hippocampus of mice. However, ketamine rapidly acts to re-establish glutamatergic synaptic efficacy via postsynaptic signaling and behaviorally masks the reduction in passive coping induced by physostigmine. These results underscore the divergence of synaptic signaling mechanisms underlying mood changes and antidepressant action and highlight how distinct synaptic mechanisms may underlie neuropsychiatric disorders versus their treatment.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 3
- Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance. Neuron February 5, 2025
- Synaptic basis of rapid antidepressant action. European Archives of Psychiatry and Clinical Neuroscience September 29, 2024
- The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring. Neuropsychopharmacology February 1, 2026
Cites 6
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics Annual Review of Medicine October 23, 2014
- Ketamine: Mechanisms and Relevance to Treatment of Depression. Annual Review of Medicine September 20, 2023
- A synaptic locus for TrkB signaling underlying ketamine rapid antidepressant action Cell Reports August 1, 2021
- Bridging rapid and sustained antidepressant effects of ketamine Trends in molecular medicine March 1, 2023
and 1 more in the library