Ketamine disrupts synaptic transmission by interacting at AMPA/Kainate receptor channels in neocortical neurons
Darrell Leong
cIRcle (University of British Columbia) 2009 DOI: 10.14288/1.0090892 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro electrophysiological study Peer reviewed |
|---|---|
| Population | Layer III-V large pyramidal neurons in the auditory cortex of gerbils |
| Intervention | Ketamine |
| Dose | 7 to 35 μM, 25 to 125 μM, 50 to 250 μM, 100 μM |
| Topics | Esketamine Ketamine |
| Key points | Ketamine reduced fast, CNQX-sensitive excitatory postsynaptic potentials in a concentration-dependent manner (IC50 7-35 micromolar) and increased input resistance at 25-125 micromolar, effects attributed to partial blockade of AMPA/kainate receptor channels. The authors propose that ketamine's clinical effects may involve AMPA/kainate receptor blockade in addition to NMDA receptor blockade, and possibly a third unidentified mechanism. |
Abstract
The dissociative anaesthetic, ketamine, is commonly known as a NMDA receptor channel blocker. However, additional mechanisms of action probably contribute to its various clinical effects. We asked if ketamine influences transmission via AMPA/kainate glutamate receptor channels. Using whole cell patch clamp techniques in brain slices we recorded excitatory postsynaptic potentials, evoked by electrical stimulation of axons in white matter, from pyramidal neurons in the auditory cortex of gerbils. The neurons were layer III-V large pyramidal neurons identified morphologically under an infrared differential interference contrast microscope, and electrophysiologically by virtue of their firing patterns. After blockade of the slow, NMDA receptor mediated EPSP component with APV, ketamine application produced a concentration-dependent reduction in amplitude of fast, CNQX-sensitive EPSPs. IC₅₀ values for ketamine were estimated to range from 7 to 35 μM. The reduction of subthreshold EPSP amplitudes was maintained for a long time following cessation of the ketamine application, but the amplitude recovered when firing was induced in the postsynaptic neuron during the washout period. At concentrations of 25 to 125 μM that led to a reduction of the fast EPSP amplitude ketamine caused an increase in input resistance. At higher concentrations, which ranged from 50 to 250 μM, resistance fell again towards control levels. Ketamine did not increase input resistance after CNQX blockade of AMPA and kainate receptor channels. Thus, ketamine appears to reduce synaptic excitation and membrane conductance by an incomplete blockade of AMPA and/or kainate receptor channels that are constitutively active at a low level in the slice preparation of auditory cortex. After blockade of both the NMDA and AMPA/kainate receptor channels, the membrane responded to application of 100 μM ketamine with an increase in resistance. Therefore, ketamine appears to produce an increase in resting resistance by partial blockade of AMPA/kainate receptor channels (as reported here) as well as NMDA receptor channels (as reported previously). Furthermore, complete blockade of NMDA and AMPA/kainate receptor channels with APV and CNQX revealed a third, yet unidentified ketamine effect associated with a resistance increase. Ketamine concentrations at synapses probably are within the range that attenuates glutamatergic synaptic transmission at AMPA/kainate and NMDA receptor channels during anaesthesia in human patients.
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
Cites 2
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
- A Review of the Nonmedical Use of Ketamine: Use, Users and Consequences Journal of Psychoactive Drugs December 1, 2000