Here we review evidence that the reactive oxygen species, hydrogen peroxide (H
2O
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
2O
2 generation in striatal medium spiny neurons (MSNs). The data show that (1) exogenous H
2O
2 suppresses DA release in dorsal striatum and nucleus accumbens shell and the same effect is seen with elevation of endogenous H
2O
2 levels; (2) H
2O
2 is generated downstream from glutamatergic AMPA receptor activation in MSNs, but not DA axons; (3) generation of modulatory H
2O
2 is activity dependent; (4) H
2O
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
2O
2-dependent inhibition of DA release is attenuated by enzymatic degradation of H
2O
2, but the subsecond time course is determined by H
2O
2 diffusion rate and/or K
ATP-channel kinetics. In the dorsal striatum, neuromodulatory H
2O
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
2O
2 occur in other regions and cell types, as well, consistent with the widespread expression of K
ATP and other H
2O
2-sensitive channels throughout the CNS.
Keywords:
Brain slices; dorsal striatum; fast-scan cyclic voltammetry; fluorescence imaging; transmitter release; review