Comparison of the effects of acute and chronic administration of ketamine on hippocampal oscillations: relevance for the NMDA receptor hypofunction model of schizophrenia.
Kara Kittelberger, Elizabeth E Hur, Saba Sazegar, Vidya Keshavan, Bernat Kocsis
Brain structure & function April 2012 DOI: 10.1007/s00429-011-0351-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experiment (acute and chronic pharmacological manipulation in rats) Peer reviewed |
|---|---|
| Population | Freely moving rats and urethane-anesthetized rats |
| Interventions | MK801 Ketamine |
| Duration | Chronic ketamine effects assessed 2-4 weeks after treatment; acute experiments not otherwise specified |
| Topics | Esketamine Ketamine |
| Key findings | Acute NMDA receptor antagonists increased hippocampal gamma power and shifted theta to higher frequencies, with CA1 theta power falling 24%, whereas chronic ketamine produced a steady decline in both gamma and theta oscillations 2-4 weeks after treatment and fewer detectable parvalbumin interneurons. The authors argue these differing acute and chronic profiles are consistent with oscillation abnormalities in human schizophrenia and support the NMDA receptor hypofunction hypothesis. |
Abstract
The proper organization and function of GABAergic interneuron networks is essential for many cognitive processes and abnormalities in these systems have been documented in schizophrenic patients. The memory function of the hippocampus depends on two major patterns of oscillations in the theta and gamma ranges, both requiring the intact functioning of the network of fast-firing interneurons expressing parvalbumin. We examined the ability of acute and chronic administration of NMDA receptor (NMDA-R) antagonists to recapitulate the oscillatory dysfunctions observed in schizophrenia. In freely moving rats, acute injection of MK801 or ketamine increased gamma power in both CA1 and dentate gyrus of the hippocampus. Theta peak shifted to higher frequencies whereas the average 5-10 Hz theta power decreased by 24% in CA1 and remained high in the dentate gyrus. Strong increase in CA1 gamma and decrease in theta power triggered by brainstem stimulation were found under urethane anesthesia. In contrast to acute experiments, chronic administration of ketamine caused a steady decline in both gamma and theta oscillations, 2-4 weeks after treatment. A further important difference between the two models was that the effects of acute injection were more robust than the changes after chronic treatment. Chronic administration of ketamine also leads to decrease in the number of detectable parvalbumin interneurons. Histological examination of interindividual differences indicated, however, that within the ketamine treated group a further decrease in parvalbumin neurons correlated with strengthening of oscillations. The findings are consistent with abnormalities of oscillations in human schizophrenia and further validate the NMDA-R hypofunction hypothesis.
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 14
- Ketamine alters oscillatory coupling in the hippocampus Scientific Reports August 2, 2013
- A Negative Allosteric Modulator for α5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice eNeuro 2017
- The neurophysiology of ketamine: an integrative review Reviews in the Neurosciences May 5, 2020
- Ketamine for psychotic depression: An overview of the glutamatergic system and ketamine's mechanisms associated with antidepressant and psychotomimetic effects. Psychiatry Research October 1, 2021
- Effects of NMDA receptor antagonists on working memory and gamma oscillations, and the mediating role of the GluN2D subunit. Neuropsychopharmacology May 15, 2025
and 9 more in the library
Cites 3
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Repeated phencyclidine in monkeys results in loss of parvalbumin-containing axo-axonic projections in the prefrontal cortex. Psychopharmacology June 2007
- A pharmacological model for psychosis based on N-methyl-D-aspartate receptor hypofunction: molecular, cellular, functional and behavioral abnormalities. Biological Psychiatry April 15, 2006