H2O2 signaling in the nigrostriatal dopamine pathway via ATP-sensitive potassium channels: issues and answers

The role of reactive oxygen species (ROS) as signaling agents is increasingly appreciated. Studies of ROS functions in the central nervous system, however, are only in their infancy. Using fast-scan cyclic voltammetry and fluorescence imaging in brain slices, the authors discovered that hydrogen peroxide (H2O2) is an endogenous regulator of dopamine release in the dorsal striatum. Given the key role of dopamine in motor, reward, and cognitive pathways, regulation by H2O2 has implications for normal dopamine function, as well as for dysfunction of dopamine transmission. In this review, data are summarized to show that H2O2 is a diffusible messenger in the striatum, generated downstream from glutamate receptor activation, and an intracellular signal in dopamine neurons of the substantia nigra, generated during normal pacemaker activity. The mechanism by which H2O2 inhibits dopamine release and dopamine cell activity is activation of ATP-sensitive K+ (KATP) channels. Characteristics of the neuronal and glial antioxidant networks required to permit H2O2 signaling, yet prevent oxidative damage, are also considered. Lastly, estimates of physiological H2O2 levels are discussed, and strengths and limitations of currently available methods for H2O2 detection, including fluorescence imaging using dichlorofluorescein (DCF) and the next generation of fluorescent probes, are considered.