INHIBITION BY VOLATILE ANESTHETICS OF ENDOGENOUS GLUTAMATE RELEASE FROM SYNAPTOSOMES BY A PRESYNAPTIC MECHANISM

Background: Synaptic transmission is more sensitive than axonal conduc tion to the effects of general anesthetics. Previous studies of the sy naptic effects of general anesthetics have focused on postsynaptic sit es of action. We now provide direct biochemical evidence for a presyna ptic effect of volatile anesthetics on neurotransmitter release. Metho ds: Rat cerebrocortical synaptosomes (isolated presynaptic nerve termi nals) were used to determine the effects of general anesthetics on the release of endogenous L-glutamate, the major fast excitatory neurotra nsmitter. nasal and evoked (by 4-aminopyridine, veratridine, increased KCl, or ionomycin) glutamate release were measured by continuous enzy me-coupled fluorometry. Results: Clinical concentrations of volatile h alogenated anesthetics, but not of pentobarbital, inhibited 4-aminopyr idine-evoked Ca2+-dependent glutamate release. Halothane also Inhibite d veratridine-evoked glutamate release but not basal, KCl-evoked, or i onomycin-evoked glutamate release. Halothane inhibited both the 4-amin opyridine-evoked and the KCl-evoked increase in free intrasynaptosomal [Ca2+]. Conclusions. Inhibition of glutamate release from presynaptic nerve terminals is a potential mechanism of volatile anesthetic actio n. Comparison of the sensitivity of glutamate release evoked by secret ogogues that act at various steps in the neurotransmitter release proc ess suggests that halothane does not affect Ca2+-secretion coupling or vesicle exocytosis but inhibits glutamate release at a step proximal to Ca2+ influx, perhaps by blocking presynaptic Na+ channels. Synaptos omal glutamate release evoked by 4-aminopyridine should provide a usef ul system for further characterization of the presynaptic effects of a nesthetics.