Enhancement by Propofol of the γ-Aminobuiyric AcidA Response in Dissociated Hippocampal Pyramidal Neurons of the Rat

Abstract

Activation of the gamma-aminobutyric acidA (GABAA) 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. 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. 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). Propofol at clinically relevant concentrations enhances the inhibitory GABAA 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.