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The Journal of Neuroscience, April 1, 2003, 23(7):2744

Glutamate-Dependent Inhibition of Dopamine Release in Striatum Is Mediated by a New Diffusible Messenger, H₂O₂

Marat V. Avshalumov, Billy T. Chen, Sarah P. Marshall, Dianna M. Peña, and Margaret E. Rice

Departments of Physiology and Neuroscience and Neurosurgery, New York University School of Medicine, New York, New York 10016

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 GABA_A-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 GABA_A-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.

Key words: dopamine; GABA; glutamate; glutathione peroxidase; catalase; Parkinson's disease; reactive oxygen species

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2372744-07$05.00/0

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