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Effects of Isoflurane on Dopamine Synaptic Vesicle Exocytosis

Although volatile anesthetics are extensively used in clinical medicine and animal research, their exact mechanism of action is not completely understood. Previous results from our laboratory show that isoflurane, a commonly used volatile anesthetic, attenuates synaptic transmission by differentially inhibiting synaptic vesicle exocytosis. Most research has been focused on glutamatergic and GABAergic neurons, while little is known of other types of neurons. Dopaminergic neurons play important roles in cognition, attention, reward, and movement, and have been implicated in emergence from anesthesia. Here we test the hypothesis that isoflurane inhibits synaptic dopamine release. Live‐cell imaging of cultured rat dopaminergic neurons were used to study action potential‐evoked exocytosis and Ca2+ influx measured by using optical methods. Neurons were transfected with a pH‐sensitive variant of GFP (pHluorin) fused to the luminal domain of the vesicular monoamine transporter (vMAT) to monitor exocytosis, or were treated with the cell permeant calcium indicator Fluo‐5F. The roles of specific Na+ and Ca2+ channel subtypes mediating the inhibition of Ca2+ influx and exocytosis are assessed using both pharmacological and genetic approaches for comparison to the effects on other synaptic vesicle phenotypes. Preliminary evidence indicates that clinical concentrations of isoflurane reduce Ca2+ influx and synaptic vesicle exocytosis. The goal of this work is to discern the molecular targets for the inhibitory effects of isoflurane on synaptic vesicle exocytosis and to elucidate additional presynaptic mechanisms of anesthetic action.