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 Peer reviewed DOI: 10.1016/j.nbd.2012.05.003 via DOAJ
Summary
Subchronic ketamine exposure in mice leads to significant long-term cognitive impairments, including disruptions in reversal learning and spatial memory, even after six months of abstinence. While there were no signs of neuronal degeneration, changes included increased astrocyte proliferation and decreased expression of the GLT-1 glutamate transporter. Event-related potentials (ERPs) and EEG measures indicated altered brain function associated with these cognitive deficits.
Study at a glance
| Population | mice exposed to subchronic ketamine |
|---|---|
| Key finding | Ketamine-treated mice exhibited lasting cognitive impairments and changes in brain function, including reduced amplitude in ERP components and altered EEG oscillations. |
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.