Presynaptic inhibition of the release of multiple major central nervous system neurotransmitter types by the inhaled anaesthetic isoflurane.

Presynaptic effects of general anaesthetics are not well characterized. We tested the hypothesis that isoflurane exhibits transmitter-specific effects on neurotransmitter release from neurochemically and functionally distinct isolated mammalian nerve terminals. Nerve terminals from adult male rat brain were prelabelled with [(3)H]glutamate and [(14)C]GABA (cerebral cortex), [(3)H]norepinephrine (hippocampus), [(14)C]dopamine (striatum), or [(3)H]choline (precursor of [(3)H]acetylcholine; striatum). Release evoked by depolarizing pulses of 4-aminopyridine (4AP) or elevated KCl was quantified using a closed superfusion system. Isoflurane at clinical concentrations (<0.7 mM; ~2 times median anaesthetic concentration) inhibited Na(+) channel-dependent 4AP-evoked release of the five neurotransmitters tested in a concentration-dependent manner. Isoflurane was a more potent inhibitor [expressed as IC(50) (SEM)] of glutamate release [0.37 (0.03) mM; P<0.05] compared with the release of GABA [0.52 (0.03) mM], norepinephrine [0.48 (0.03) mM], dopamine [0.48 (0.03) mM], or acetylcholine [0.49 (0.02) mM]. Inhibition of Na(+) channel-independent release evoked by elevated K(+) was not significant at clinical concentrations of isoflurane, with the exception of dopamine release [IC(50)=0.59 (0.03) mM]. Isoflurane inhibited the release of the major central nervous system neurotransmitters with selectivity for glutamate release, consistent with both widespread inhibition and nerve terminal-specific presynaptic effects. Glutamate release was most sensitive to inhibition compared with GABA, acetylcholine, dopamine, and norepinephrine release due to presynaptic specializations in ion channel expression, regulation, and/or coupling to exocytosis. Reductions in neurotransmitter release by volatile anaesthetics could contribute to altered synaptic transmission, leading to therapeutic and toxic effects involving all major neurotransmitter systems.