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

Background: Activation of the gamma-aminobutyric acid(A) (GABA(A)) rec eptor-ionophore complex has been reported as a possible molecular mech anism of the anesthetic action of propofol. Augmentation of GABA-induc ed inhibitory transmission has also been suggested as a mechanism. Bec ause data describing this latter mechanism in mammalian neurons are fe w, we have examined the effects of propofol on the GABA response in ce ntral neurons of the rat. Methods: Hippocampal pyramidal neurons were dissociated after enzyme treatment of the rat brain slices. The neuron s 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 th e neuron within 10-20 ms and makes it possible to obtain the peak resp onse before desensitization develops. Results: In pyramidal neurons vo ltage-clamped at -60 mV, GABA induced an inward current. Propofol (10( -6) M) augmented the current and shifted the concentration-response cu rve for GABA to the left without affecting the maximum response. A low concentration of the anesthetic (10(-6) M) reduced the dissociation c onstant for GABA from 8.2 X 10(-6) to 4.2 X 10(-6) M without a signifi cant effect on the Hill coefficient. Coapplication of propofol at a hi gher 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 re versal 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 concen trations enhances the inhibitory GABA(A) receptor-mediated response in mammalian central neurons. The enhancement may result in reduced exci tability of the neuronal network and may, consequently, contribute to the anesthetic action of the agent.