Glutamate-dependent inhibition of dopamine release in striatum is mediated by a new diffusible messenger, H2O2.
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 (H(2)O(2)). 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 H(2)O(2)-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 H(2)O(2) 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 H(2)O(2) 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 H(2)O(2) is generated in non-DA cells. Thus, in addition to its known excitatory actions in striatum, glutamate mediates inhibition by generating H(2)O(2) 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.
Avshalumov
Marat V
MV
Department of Physiology, New York University School of Medicine, New York, New York 10016, USA.
Chen
Billy T
BT
Marshall
Sarah P
SP
Peña
Dianna M
DM
Rice
Margaret E
ME
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001569:Benzodiazepines; D002450:Cell Communication; D002478:Cells, Cultured; D004058:Diffusion; D004298:Dopamine / Q000378:metabolism*; D004558:Electric Stimulation; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology*; D006168:Guinea Pigs; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D015221:Potassium Channels / Q000502:physiology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D014151:Anti-Anxiety Agents; D018756:GABA Antagonists; D015221:Potassium Channels; D018091:Receptors, AMPA; C061950:GYKI 52466; D001569:Benzodiazepines; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D006861:Hydrogen Peroxide; D004298:Dopamine