Ketamine-induced neurotoxicity and changes in gene expression in the developing rat brain.
Fang Liu, Merle G. Paule, Syed F. Ali, Cheng Z Wang
Current Neuropharmacology March 2011 DOI: 10.2174/157015911795017155 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Postnatal day 7 (PND-7) rat pups |
| Intervention | Ketamine |
| Dose | 5, 10, or 20 mg/kg subcutaneously in one, three, or six injections |
| Topics | Ketamine Esketamine |
| Keywords | N-methyl-d-aspartate nmda receptor Apoptosis In situ hybridization Microarray analysis. |
| Key findings | Six subcutaneous injections of 20 mg/kg ketamine significantly increased apoptotic neuronal cell death in the frontal cortex of PND-7 rat pups, while lower doses and fewer injections did not. The authors suggest this reflects compensatory up-regulation of NMDA receptors, with increased NR1 subunit expression and altered apoptotic gene expression, that subsequently triggers apoptosis in developing neurons. |
Abstract
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used for analgesia and anesthesia in obstetric and pediatric practice. Recent reports indicate that ketamine causes neuronal cell death in developing rodents and nonhuman primates. The present study assessed the potential dose- and time-dependent neurotoxic effects and associated changes in gene expression after ketamine administration to postnatal day 7 (PND-7) rat pups. Pups were exposed to ketamine subcutaneously at doses of 5, 10, or 20 mg/kg, in one, three or six injections respectively. Control animals received the same volume of saline at the same time points. The animals were sacrificed 6 h after the last ketamine or saline administration and brain tissues were collected for RNA isolation and histochemical examination. Six injections of 20 mg/kg ketamine significantly increased neuronal cell death in frontal cortex, while lower doses and fewer injections did not show significant effects. The ketamine induced cell death seemed to be apoptotic in nature. In situ hybridization demonstrated that NMDA receptor NR1 subunit expression was dramatically increased in the frontal cortex of ketamine treated rats. Microarray analysis revealed altered expression of apoptotic relevant genes and increased NMDA receptor gene expression in brains from ketamine treated animals. Quantitative RT-PCR confirmed the microarray results. These data suggest that repeated exposures to high doses of ketamine can cause compensatory up-regulation of NMDA receptors and subsequently trigger apoptosis in developing neurons.
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 9
- Ketamine use disorder: preclinical, clinical, and neuroimaging evidence to support proposed mechanisms of actions Intelligent Medicine March 7, 2022
- Ketamine for Depression, but at What Cost? A Review of Ketamine’s Neurotoxic Effects From Preclinical and Human Studies American Journal of Psychiatry September 10, 2025
- Real-world effectiveness of repeated intravenous ketamine infusions for treatment-resistant depression in transitional age youth Journal of Psychopharmacology May 16, 2023
- The Involvement of the Serotonergic System in Ketamine and Fluoxetine Combination-induced Cognitive Impairments in Mice. The Eurasian journal of medicine June 1, 2024
- An integrative model of ketamine-induced memory dysfunction: From synapse to circuit in clinical context. Neurotoxicology August 30, 2026
and 4 more in the library