New Hippocampal Neurons Mature Rapidly in Response to Ketamine But Are Not Required for Its Acute Antidepressant Effects on Neophagia in Rats
A. Soumier, Ray M. Carter, Timothy J. Schoenfeld, H. Cameron
eNeuro March 1, 2016 DOI: 10.1523/eneuro.0116-15.2016 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Rats, including a long-term corticosterone administration depression model and controls |
| Intervention | S-ketamine (S-(+)-ketamine hydrochloride) |
| Duration | At least 4 weeks |
| Measures | zif268, proliferating cell nuclear antigen, BrdU |
| Topics | Esketamine Ketamine |
| Key findings | A single S-ketamine injection rapidly increased the proportion of functionally mature young dentate gyrus granule neurons within 2 hours and increased cell proliferation and functional maturation while decreasing depressive-like behavior for at least 4 weeks in rats. The authors conclude that ketamine has rapid and long-lasting effects on recruiting young neurons into hippocampal networks, but that its antidepressant-like behavioral effects are independent of adult neurogenesis. |
Abstract
Abstract Virtually all antidepressant agents increase the birth of granule neurons in the adult dentate gyrus in rodents, providing a key basis for the neurogenesis hypothesis of antidepressant action. The novel antidepressant ketamine, however, shows antidepressant activity in humans within hours, far too rapid for a mechanism involving neuronal birth. Ketamine could potentially act more rapidly by enhancing maturation of new neurons born weeks earlier. To test this possibility, we assessed the effects of S-ketamine (S-(+)-ketamine hydrochloride) injection on maturation, as well as birth and survival, of new dentate gyrus granule neurons in rats, using the immediate-early gene zif268, proliferating cell nuclear antigen, and BrdU, respectively. We show that S-ketamine has rapid effects on new neurons, increasing the proportion of functionally mature young granule neurons within 2 h. A single injection of S-ketamine also increased cell proliferation and functional maturation, and decreased depressive-like behavior, for at least 4 weeks in rats treated with long-term corticosterone administration (a depression model) and controls. However, the behavioral effects of S-ketamine on neophagia were unaffected by elimination of adult neurogenesis. Together, these results indicate that ketamine has surprisingly rapid and long-lasting effects on the recruitment of young neurons into hippocampal networks, but that ketamine has antidepressant-like effects that are independent of adult neurogenesis.
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 27
- Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine. Pharmacology, Biochemistry, and Behavior December 9, 2019
- Ketamine: Mechanisms and Relevance to Treatment of Depression. Annual Review of Medicine September 20, 2023
- Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice Nature Communications May 12, 2022
- An Integrative Approach to Ketamine Therapy May Enhance Multiple Dimensions of Efficacy: Improving Therapeutic Outcomes With Treatment Resistant Depression. Frontiers in Psychiatry November 24, 2021
- Is (R)-ketamine a Potential Therapeutic Agent for Treatment-Resistant Depression with Less Detrimental Side Effects? A Review of Molecular Mechanisms Underlying Ketamine and its Enantiomers. Biochemical Pharmacology February 1, 2022
and 22 more in the library
Cites 14
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NEUROBIOLOGY OF STRESS, DEPRESSION, AND RAPID ACTING ANTIDEPRESSANTS: REMODELING SYNAPTIC CONNECTIONS Depression and Anxiety March 10, 2014
- Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review Therapeutic Advances in Chronic Disease April 13, 2015
- Ketamine as a promising prototype for a new generation of rapid‐acting antidepressants Annals of the New York Academy of Sciences February 27, 2015
- Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade Frontiers in Molecular Neuroscience September 11, 2015
and 9 more in the library