ENHANCEMENT BY PROPOFOL OF THE GAMMA-AMINOBUTYRIC ACID(A) RESPONSE IN DISSOCIATED HIPPOCAMPAL PYRAMIDAL NEURONS OF THE RAT

Background: Activation of the gamma-aminobutyric acid(A) (GABA(A)) receptor-ionophore complex has been reported as a possible molecular mechanism of the anesthetic action of propofol. Augmentation of GABA-induced inhibitory transmission has also been suggested as a mechanism. Because data describing this latter mechanism in mammalian neurons are few, we have examined the effects of propofol on the GABA response in central neurons of the rat. Methods: Hippocampal pyramidal neurons were dissociated after enzyme treatment of the rat brain slices. The neurons were voltage-clamped with the whole cell configuration of the patch clamp technique. Neurotransmitters and drugs were applied using the ''Y-tube'' method, which exchanges the extracellular solutions around the neuron within 10-20 ms and makes it possible to obtain the peak response before desensitization develops. Results: In pyramidal neurons voltage-clamped at -60 mV, GABA induced an inward current. Propofol (10(-6) M) augmented the current and shifted the concentration-response curve for GABA to the left without affecting the maximum response. A low concentration of the anesthetic (10(-6) M) reduced the dissociation constant for GABA from 8.2 X 10(-6) to 4.2 X 10(-6) M without a significant effect on the Hill coefficient. Coapplication of propofol at a higher concentration (5 X 10(-6) M) also shifted the GABA dose-response curve to the left, reducing the dissociation constant to 2.8 X 10(-6) M. Potentiation by propofol was not associated with a change in the reversal potential for the GABA response and was not voltage-dependent. The inhibitory glycine response was not affected by propofol (10(-6) M or 5 X 10(-6) M). Conclusions: Propofol at clinically relevant concentrations enhances the inhibitory GABA(A) receptor-mediated response in mammalian central neurons. The enhancement may result in reduced excitability of the neuronal network and may, consequently, contribute to the anesthetic action of the agent.