Glutamate-dependent inhibition of dopamine release in striatum is mediated by a new diffusible messenger, H2O2

Abstract

How glutamate regulates dopamine (DA) release in striatum has been a controversial issue. Here, we resolve this by showing that glutamate, acting at AMPA receptors, inhibits DA release by a nonclassic mechanism mediated by hydrogen peroxide (H2O2). Moreover, we show that GABAA-receptor activation opposes this process, thereby enhancing DA release. The influence of glutamate and GABA on DA release was assessed in striatal slices using carbon-fiber microelectrodes and fast-scan cyclic voltammetry. Modulation by both transmitters was prevented by H2O2-metabolizing enzymes. In addition, the influence of GABAA-receptor activation was lost when AMPA receptors were blocked with GYKI-52466. Together, these data show that modulation of DA release by glutamate and GABA depends on H2O2 generated downstream from AMPA receptors. This is the first evidence that endogenous glutamate can lead to the generation of reactive oxygen species under physiological conditions. We also show that inhibition of DA release by H2O2 is mediated by sulfonylurea-sensitive K+ channels: tolbutamide blocked DA modulation by glutamate and by GABA. The absence of ionotropic glutamate or GABA receptors on DA terminals indicates that modulatory H2O2 is generated in non-DA cells. Thus, in addition to its known excitatory actions in striatum, glutamate mediates inhibition by generating H2O2 that must diffuse from postsynaptic sites to inhibit presynaptic DA release via K+-channel opening. These findings have significant implications not only for normal striatal function but also for understanding disease states that involve DA and oxidative stress, including disorders as diverse as Parkinson's disease and schizophrenia.