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 (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.

N-Methyl-d-aspartate Modulation of Nucleus Accumbens Dopamine Release by Metabotropic Glutamate Receptors: Fast Cyclic Voltammetry Studies in Rat Brain Slices in Vitro

“…However, the dosedependency of the effect was confirmed across the three concentrations tested through the highly significant linear trend in response suppression with concentration. These data support previous findings that agonists at ionotropic glutamate receptors generally 27,28 and specifically NMDA-R 12,24 in dorsal striatum caused a decrease in stimulated dopamine, across a similar dose range, albeit that unlike those of Wu et al…”

α6-Containing Nicotinic Acetylcholine Receptors Dominate the Nicotine Control of Dopamine Neurotransmission in Nucleus Accumbens

“…Evoked DA release on the timescale of these experiments is not modulated by glutamate or GABA at ionotropic receptors (Avshalumov et al, 2003;Cragg, 2003), or DA D 2 receptors (Cragg, 2003). However, DA release is governed by a basal tone of endogenous ACh acting at presynaptic nAChRs on DA axons (Rice and Cragg, 2004;Zhang and Sulzer, 2004;Zhou et al, 2001).…”

Nitric oxide mediates glutamate-evoked dopamine release in the medial preoptic area

“…Both basal (Lorrain and Hull, 1993) and copulation-stimulated (Lorrain et al, 1996) DA release in the MPOA is regulated, at least in part, by nitric oxide (NO). However, factors "upstream" of NO have not been determined.Glutamate regulates the release of DA in several brain regions both in vitro and in vivo (Whitton, 1997;Takahata and Moghaddam, 1998;Verma and Moghaddam, 1998;Shimazoe et al, 2002;Howland et al, 2002;Avshalumov et al, 2003;Katayama et al, 2003;Morikawa et al, 2003). The present experiments investigated the effects of exogenous glutamate on extracellular DA in the MPOA of male rats.…”

“…Glutamate regulates the release of DA in several brain regions both in vitro and in vivo (Whitton, 1997;Takahata and Moghaddam, 1998;Verma and Moghaddam, 1998;Shimazoe et al, 2002;Howland et al, 2002;Avshalumov et al, 2003;Katayama et al, 2003;Morikawa et al, 2003). Glutamate-DA interactions have been implicated in the regulation of various behaviors and behavioral disorders, including drug addiction (reviewed in Kelley and Berridge, 2002), schizophrenia (reviewed in Carlsson et al 2001;Moghaddam, 2002;Pralong et al, 2002), and Parkinson's disease (reviewed in Carlsson and Carlsson, 1990;Lange et al, 1997).…”