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Ketamine disrupts synaptic transmission by interacting at AMPA/Kainate receptor channels in neocortical neurons

University of British Columbia

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.

Thesis/Dissertation

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2009-10-17

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http://hdl.handle.net/2429/13936

Pharmacology

University of British Columbia

UBCV

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