The influence of propofol, a new intravenous anesthetic agent, on brain gamma-aminobutyric acid (GABA)-ergic transmission has been investigated both in vitro and in vivo. In vitro, propofol, like benzodiazepines, 1) markedly enhanced 3H-GABA binding in cortical membrane preparations; 2) potentiated muscimol-induced stimulation of 36Cl- uptake in membrane vesicle preparations (the propofol potentiating effect was antagonized by bicuculline); and 3) inhibited 35S-TBPS binding to unwashed membrane preparations from rat cerebral cortex. Finally, propofol failed to displace 3H-flunitrazepam from its binding site, indicating that its site of action in brain is different from that of benzodiazepines. In vivo, the effect of propofol was studied using single-unit recording of the electrical activity of both nondopaminergic neurons in the pars reticulata of the substantia nigra (PR neurons) and of dopaminergic neurons in the pars compacta of the substantia nigra (DA neurons). PR neurons are known to be inhibited by GABA-mimetic drugs and benzodiazepines, whereas DA neurons are tonically inhibited by PR neurons. The intravenous administration of propofol, in a fat emulsion formulation, produced a brief dose-dependent inhibition of the firing rate of PR neurons. The dose producing 50% inhibition of the firing rate was calculated to be 1.2 +/- 0.1 mg/kg. The inhibitory effect lasted less than 5 min. Repeated injections of propofol reproduced the same inhibitory response, whereas continuous infusion (0.5 mg.kg-1.min-1) produced a persistent inhibition of neuronal firing. The inhibitory effect of propofol on PR neurons was potentiated by diazepam and reversed by picrotoxin and bicuculline but was not influenced by the benzodiazepine antagonist Ro 15-1788. These findings suggest that propofol exerts a GABA-mimetic action on PR neurons by acting on a site distinct from the benzodiazepine recognition site. Unlike benzodiazepines, propofol inhibited the firing rate of DA neurons with a potency proportional to its inhibitory effect on PR neurons. The inhibition of DA neurons was reversed by bicuculline and picrotoxin. The results suggest that propofol enhances the inhibitory control over DA neurons by strionigral GABAergic neurons.
Biochemical and electrophysiologic evidence that propofol enhances GABAergic transmission in the rat brain.
CONCAS, ALESSANDRA;
1991-01-01
Abstract
The influence of propofol, a new intravenous anesthetic agent, on brain gamma-aminobutyric acid (GABA)-ergic transmission has been investigated both in vitro and in vivo. In vitro, propofol, like benzodiazepines, 1) markedly enhanced 3H-GABA binding in cortical membrane preparations; 2) potentiated muscimol-induced stimulation of 36Cl- uptake in membrane vesicle preparations (the propofol potentiating effect was antagonized by bicuculline); and 3) inhibited 35S-TBPS binding to unwashed membrane preparations from rat cerebral cortex. Finally, propofol failed to displace 3H-flunitrazepam from its binding site, indicating that its site of action in brain is different from that of benzodiazepines. In vivo, the effect of propofol was studied using single-unit recording of the electrical activity of both nondopaminergic neurons in the pars reticulata of the substantia nigra (PR neurons) and of dopaminergic neurons in the pars compacta of the substantia nigra (DA neurons). PR neurons are known to be inhibited by GABA-mimetic drugs and benzodiazepines, whereas DA neurons are tonically inhibited by PR neurons. The intravenous administration of propofol, in a fat emulsion formulation, produced a brief dose-dependent inhibition of the firing rate of PR neurons. The dose producing 50% inhibition of the firing rate was calculated to be 1.2 +/- 0.1 mg/kg. The inhibitory effect lasted less than 5 min. Repeated injections of propofol reproduced the same inhibitory response, whereas continuous infusion (0.5 mg.kg-1.min-1) produced a persistent inhibition of neuronal firing. The inhibitory effect of propofol on PR neurons was potentiated by diazepam and reversed by picrotoxin and bicuculline but was not influenced by the benzodiazepine antagonist Ro 15-1788. These findings suggest that propofol exerts a GABA-mimetic action on PR neurons by acting on a site distinct from the benzodiazepine recognition site. Unlike benzodiazepines, propofol inhibited the firing rate of DA neurons with a potency proportional to its inhibitory effect on PR neurons. The inhibition of DA neurons was reversed by bicuculline and picrotoxin. The results suggest that propofol enhances the inhibitory control over DA neurons by strionigral GABAergic neurons.
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