H2O2 Is a Novel, Endogenous Modulator of Synaptic Dopamine Release

Abstract

Recent evidence suggests that reactive oxygen species (ROS) might act as modulators of neuronal processes, including synaptic transmission. Here we report that synaptic dopamine (DA) release can be modulated by an endogenous ROS, H2O2. Electrically stimulated DA release was monitored in guinea pig striatal slices using carbon-fiber microelectrodes with fast-scan cyclic voltammetry. Exogenously applied H2O2reversibly inhibited evoked release in the presence of 1.5 mM Ca2+. The effectiveness of exogenous H2O2, however, was abolished or decreased by conditions that enhance Ca2+ entry, including increased extracellular Ca2+ concentration ([Ca2+]o; to 2.4 mM), brief, high-frequency stimulation, and blockade of inhibitory D2 autoreceptors. To test whether DA release could be modulated by endogenous H2O2, release was evoked in the presence of the H2O2-scavenging enzyme, catalase. In the presence of catalase, evoked [DA]o was 60% higher than after catalase washout, demonstrating that endogenously generated H2O2 can also inhibit DA release. Importantly, the Ca2+ dependence of the catalase-mediated effect was opposite to that of H2O2: catalase had a greater enhancing effect in 2.4 mM Ca2+ than in 1.5 mM, consistent with enhanced H2O2 generation in higher [Ca2+]o. Together these data suggest that H2O2production is Ca2+ dependent and that the inhibitory mechanism can be saturated, thus preventing further effects from exogenous H2O2. These findings show for the first time that endogenous H2O2 can modulate vesicular neurotransmitter release, thus revealing an important new signaling role for ROS in synaptic transmission.