H2O2 is a novel, endogenous modulator of synaptic dopamine release

Recent evidence suggests that reactive oxygen species (ROS) might act as mo dulators of neuronal processes, including synaptic transmission. Here we re port that synaptic dopamine (DA) release can be modulated by an endogenous ROS, H2O2. Electrically stimulated DA release was monitored in guinea pig s triatal slices using carbon-fiber microelectrodes with fast-scan cyclic vol tammetry. Exogenously applied H2O2 reversibly inhibited evoked release in t he presence of 1.5 mM Ca2+. The effectiveness of exogenous H2O2, however, w as abolished or decreased by conditions that enhance Ca2+ entry, including increased extracellular Ca2+ concentration ([Ca2+](o); to 2.4 mM), brief, h igh frequency stimulation, and blockade of inhibitory D-2 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 pre sence of catalase, evoked [DA](o) was 60% higher than after catalase washou t, demonstrating that endogenously generated H2O2 can also inhibit DA relea se. Importantly, the Ca2+ dependence of the catalase-mediated effect was op posite to that of H2O2: catalase had a greater enhancing effect in 2.4 mM C a2+ than in 1.5 mM, consistent with enhanced H2O2 generation in higher [Ca2 +](o). Together these data suggest that H2O2 production is Ca2+ dependent a nd that the inhibitory mechanism can be saturated, thus preventing further effects from exogenous H2O2. These findings show for the first time that en dogenous H2O2 can modulate vesicular neurotransmitter release, thus reveali ng an important new signaling role for ROS in synaptic transmission.