Subchronic ketamine treatment leads to permanent changes in EEG, cognition and the astrocytic glutamate transporter EAAT2 in mice
Robert E. Featherstone, Yuling Liang, John A. Saunders, Valerie M. Tatard-Leitman, Richard S. Ehrlichman, Steven J. Siegel
Neurobiology of Disease March 22, 2021 DOI: 10.1016/j.nbd.2012.05.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled laboratory experiment Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Ketamine |
| Duration | 6-month period of abstinence following subchronic ketamine exposure |
| Topics | Esketamine Ketamine |
| Keywords | Nmda Gfap Schizophrenia Eaat Glt-1 Auditory evoked potential |
| Citations | 75 |
| Key findings | Subchronic ketamine in mice caused lasting reductions in N40 and P80 ERP components, decreased theta oscillations, and impairments in reversal learning and spatial memory, along with increased astrocyte proliferation and reduced GLT-1 expression, without neuronal degeneration. |
Abstract
Ketamine is an NMDA receptor antagonist with psychotomimetic, dissociative, amnestic and euphoric effects. When chronically abused, ketamine users display deficits in cognition and information processing, even following long-term abstinence from the drug. While animal studies have shown evidence of behavioral changes and cognitive deficits that mimic those seen in humans within the period immediately following subchronic ketamine, a few animal studies have assessed long-term changes following cessation of ketamine exposure. To this end, the present study assessed event related potentials (ERPs) and EEG oscillations in mice exposed to subchronic ketamine following a 6 month period of abstinence from the drug. Ketamine-treated mice showed no change in P20, but did show marked reductions in amplitude of the later N40 and P80 components, consistent with previous studies of acute ketamine exposure. Additionally, ketamine-treated animals showed a significant reduction in stimulus evoked theta oscillations. To assess the functional significance of these changes, mice were also assessed on a series of behavioral and cognitive tests, including progressive ratio (motivation), extinction (behavioral flexibility) and win-shift radial maze (spatial memory). Subchronic ketamine produced marked disruptions in reversal learning and spatial memory. Analysis of brains from ketamine-treated mice failed to show evidence of neuronal degeneration as determined by NueN immunohistochemistry, but did show increased astrocyte proliferation and decreased expression of the glial specific glutamate transporter, GLT-1. These results strongly suggest: 1) that subchronic ketamine induces significant changes in brain function that long exceed exposure to the drug; 2) that ketamine exposure in mice induces lasting cognitive impairments closely resembling those observed in human ketamine abusers; 3) that ERP and EEG measures are highly sensitive to alterations in brain function associated with reduced cognitive function; and 4) that the brain changes induced by chronic ketamine treatment are suggestive of long-term adaptive or plastic, rather than degenerative, changes.
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 13
- Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression Psychotherapy and Psychosomatics 2017
- On the safety of repeated ketamine infusions for the treatment of depression: Effects of sex and developmental periods Neurobiology of Stress September 21, 2018
- 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
- Delayed emergence of behavioral and electrophysiological effects following juvenile ketamine exposure in mice Translational Psychiatry September 15, 2015
- Psychedelic assisted therapy for major depressive disorder: Recent work and clinical directions Journal of Psychedelic Studies June 9, 2022
and 8 more in the library
Cites 9
- Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase Science December 6, 2007
- Attenuation of the Neuropsychiatric Effects of Ketamine With Lamotrigine Archives of General Psychiatry March 1, 2000
- Glutamate and the Neural Basis of the Subjective Effects of Ketamine Archives of General Psychiatry February 1, 2008
- Club drugs: methylenedioxymethamphetamine, flunitrazepam, ketamine hydrochloride, and gamma-hydroxybutyrate American Journal of Health-System Pharmacy June 1, 2002
- Ketamine Disrupts Frontal and Hippocampal Contribution to Encoding and Retrieval of Episodic Memory: An fMRI Study Cerebral Cortex November 10, 2004
and 4 more in the library