Abstract
Ketamine is a clinical anesthetic and antidepressant. Although ketamine is a known NMDA receptor antagonist, the mechanisms contributing to antidepression are unclear. This present study examined the loci and duration of ketamine’s actions, and the involvement of NMDA receptors. Local field potentials were recorded from the CA1 region of mouse hippocampal slices. Ketamine was tested at antidepressant and anesthetic concentrations. Effects of NMDA receptor antagonists APV and MK-801, GABA receptor antagonist bicuculline, and a potassium channel blocker TEA were also studied. Ketamine decreased population spike amplitudes during application, but a long-lasting increase in amplitudes was seen during washout. Bicuculline reversed the acute effects of ketamine, but the washout increase was not altered. This long-term increase was statistically significant, sustained for >2 h, and involved postsynaptic mechanisms. A similar effect was produced by MK-801, but was only partially evident with APV, demonstrating the importance of the NMDA receptor ion channel block. TEA also produced a lasting excitability increase, indicating a possible involvement of potassium channel block. This is this first report of a long-lasting increase in excitability following ketamine exposure. These results support a growing literature that increased GABA inhibition contributes to ketamine anesthesia, while increased excitatory transmission contributes to its antidepressant effects.
Highlights
Ketamine is an anesthetic, utilized in clinical settings since 1970 [1,2]
Some evidence suggests that ketamine’s antidepressant effects are due to a blockade of NMDA receptors producing a downregulation of eukaryotic elongation factor 2 kinase and the subsequent enhancement of brain-derived neurotrophic factor (BDNF) expression [4,5]
We tested concentrations of ketamine at 10 μM [4,5] and 350 μM [22] on Population Spike (PS) recorded from mouse hippocampal slices (Figure 1)
Summary
Ketamine is an anesthetic, utilized in clinical settings since 1970 [1,2]. It has been shown to produce amnestic, analgesic, and anti-inflammatory effects [2]. Some evidence suggests that ketamine’s antidepressant effects are due to a blockade of NMDA receptors producing a downregulation of eukaryotic elongation factor 2 (eEF2) kinase and the subsequent enhancement of brain-derived neurotrophic factor (BDNF) expression [4,5]. This results in an increased α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor insertion on the postsynaptic membrane leading to synaptic potentiation, protein synthesis and synaptogenesis [4,5,16]. With its well-defined lamellar structure of glutamatergic and GABAergic synapses, the hippocampus provided a model to explore these effects of ketamine [20,21]
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