INHIBITION BY PROPOFOL-(2,6-DI-ISOPROPYLPHENOL) OF THE N-METHYL-D-ASPARTATE SUBTYPE OF GLUTAMATE-RECEPTOR IN CULTURED HIPPOCAMPAL-NEURONS

1 The effects of propofol (2,6 di-isopropylphenol) on responses to the selective glutamate receptor agonists, N-methyl-D-aspartate (NMDA) an d kainate, were investigated in cultured hippocampal neurones of the m ouse. Whole cell and single channel currents were recorded by patch-cl amp techniques. Drugs were applied with a multi-barrel perfusion syste m. 2 Propofol produced a reversible, dose-dependent inhibition of whol e cell currents activated by NMDA. The concentration of propofol which induced 50% of the maximal inhibition (IC50) was approximately 160 mu M. The maximal inhibition was incomplete leaving a residual current o f about 33% of the control response. This inhibitory action of propofo l was neither voltage- nor use-dependent. 3 Analysis of the dose-respo nse relation for whole cell NMDA-activated currents indicated that pro pofol caused no significant change in the apparent affinity of the rec eptor for NMDA. 4 Outside-out patch recordings of single channel curre nts evoked by NMDA (10 mu M) revealed that propofol (100 mu M) reversi bly decreased the probability of channel opening but did not influence the average duration of channel opening or single channel conductance . 5 Whole-cell currents evoked by kainate (50 mu M) were insensitive t o propofol (1 mu M - 1 mM). 6 These results indicate that propofol inh ibits the NMDA subtype of glutamate receptor, possibly through an allo steric modulation of channel gating rather than by blocking the open c hannel. Depression of NMDA-mediated excitatory neurotransmission may c ontribute to the anaesthetic, amnesic and anti-convulsant properties o f propofol.