Anesthetics modulate the release of glutamate and GABA via neuronal nicotinic acetylcholine receptors

Abstract

Inhalational general anesthetics are known to modulate the activity of various neuroreceptors and ion channels. Potentiation of the GABAA receptor function and inhibition of the glutamate receptors received much attention. Recently, it is becoming abundantly clear that neuronal nicotinic acetylcholine receptors (nAChRs) are also an important target site of general anesthetics. Modulation of the presynaptic and preterminal nAChRs affects the release of various transmitters leading to amplification of the effects via a cascade of multisynaptic events. We studied the effects of isoflurane and sevoflurane on spontaneous miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in rat cortical neurons in primary culture. The currents were recorded from bipolar and multipolar neurons using the patch clamp technique. Both isoflurane and sevolfurane at 1 MAC had essentially the same effects. In bipolar neurons, the amplitude of mEPSCs was suppressed by anesthetics, while that of mIPSCs was augmented. These effects of anesthetics reflect direct inhibition and potentiation of the glutamate and GABAA receptors, respectively. The frequency of mEPSCs and mIPSCs of bipolar neurons was increased by 30 μM ACh, reflecting the increased release of glutamate and GABA, respectively, as a result of the activation of nAChRs. Anesthetics had no effect on the frequency when applied along. However, when anesthetics and ACh were co-applied, the frequency was increased less than that caused by ACh alone, presumably because anesthetics inhibited the activity of nAChRs. Multipolar neurons were devoid of nAChs and responded to ACh and anesthetics in the same way as that of bipolar neurons with the exception of the responses via nAChRs. In conclusion, isoflurane and sevoflurane modulate the activity of the glutamate and GABA receptors both directly and indirectly via inhibition of nAChRs.