Classification of H₂O₂as a neuromodulator that regulates striatal dopamine release on a subsecond time scale

Here we review evidence that the reactive oxygen species, hydrogen peroxide (H(2)O(2)), meets the criteria for classification as a neuromodulator through its effects on striatal dopamine (DA) release. This evidence was obtained using fast-scan cyclic voltammetry to detect evoked DA release in striatal slices, along with whole-cell and fluorescence imaging to monitor cellular activity and H(2)O(2) generation in striatal medium spiny neurons (MSNs). The data show that (1) exogenous H(2)O(2) suppresses DA release in dorsal striatum and nucleus accumbens shell and the same effect is seen with elevation of endogenous H(2)O(2) levels; (2) H(2)O(2) is generated downstream from glutamatergic AMPA receptor activation in MSNs, but not DA axons; (3) generation of modulatory H(2)O(2) is activity dependent; (4) H(2)O(2) generated in MSNs diffuses to DA axons to cause transient DA release suppression by activating ATP-sensitive K(+) (K(ATP)) channels on DA axons; and (5) the amplitude of H(2)O(2)-dependent inhibition of DA release is attenuated by enzymatic degradation of H(2)O(2), but the subsecond time course is determined by H(2)O(2) diffusion rate and/or K(ATP)-channel kinetics. In the dorsal striatum, neuromodulatory H(2)O(2) is an intermediate in the regulation of DA release by the classical neurotransmitters glutamate and GABA, as well as other neuromodulators, including cannabinoids. However, modulatory actions of H(2)O(2) occur in other regions and cell types, as well, consistent with the widespread expression of K(ATP) and other H(2)O(2)-sensitive channels throughout the CNS.