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PMID: 12388621 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

The origin and neuronal function of in vivo nonsynaptic glutamate.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 22 ·No. 20 ·2002-10-15 ·Pages 9134-41

Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW

Abstract

Basal extracellular glutamate sampled in vivo is present in micromolar concentrations in the extracellular space outside the synaptic cleft, and neither the origin nor the function of this glutamate is known. This report reveals that blockade of glutamate release from the cystine-glutamate antiporter produced a significant decrease (60%) in extrasynaptic glutamate levels in the rat striatum, whereas blockade of voltage-dependent Na+ and Ca2+ channels produced relatively minimal changes (0-30%). This indicates that the primary origin of in vivo extrasynaptic glutamate in the striatum arises from nonvesicular glutamate release by the cystine-glutamate antiporter. By measuring [35S]cystine uptake, it was shown that similar to vesicular release, the activity of the cystine-glutamate antiporter is negatively regulated by group II metabotropic glutamate receptors (mGluR2/3) via a cAMP-dependent protein kinase mechanism. Extracellular glutamate derived from the antiporter was shown to regulate extracellular levels of glutamate and dopamine. Infusion of the mGluR2/3 antagonist (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA) increased extracellular glutamate levels, and previous blockade of the antiporter prevented the APICA-induced rise in extracellular glutamate. This suggests that glutamate released from the antiporter is a source of endogenous tone on mGluR2/3. Blockade of the antiporter also produced an increase in extracellular dopamine that was reversed by infusing the mGluR2/3 agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxlylate, indicating that antiporter-derived glutamate can modulate dopamine transmission via mGluR2/3 heteroreceptors. These results suggest that nonvesicular release from the cystine-glutamate antiporter is the primary source of in vivo extracellular glutamate and that this glutamate can modulate both glutamate and dopamine transmission.

MeSH Terms
Animals Carrier Proteins/antagonists & inhibitors,metabolism Corpus Striatum/cytology,drug effects,metabolism Cyclic AMP-Dependent Protein Kinases/metabolism Dopamine/analysis,metabolism Excitatory Amino Acid Agonists/pharmacology Excitatory Amino Acid Antagonists/pharmacology Extracellular Space/chemistry,metabolism Glutamic Acid/analysis,metabolism In Vitro Techniques Male Microdialysis Neurons/drug effects,metabolism Rats Rats, Sprague-Dawley Receptors, Metabotropic Glutamate/agonists,antagonists & inhibitors,metabolism Synapses/metabolism Synaptic Transmission/drug effects,physiology
Chemicals
Carrier Proteins Excitatory Amino Acid Agonists Excitatory Amino Acid Antagonists Receptors, Metabotropic Glutamate metabotropic glutamate receptor 2 metabotropic glutamate receptor 3 Glutamic Acid Cyclic AMP-Dependent Protein Kinases Dopamine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Baker David A
Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425, USA. bakerda@musc.edu
Xi Zheng-Xiong
Shen Hui
Swanson Chad J
Kalivas Peter W
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Email
bakerda@musc.edu
Published
2002-10-15
Pages
9134-41
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6757683
Subset
IM
Grants
NIMH NIH HHS · R01 MH040817 · United States
NIDA NIH HHS · DA-06074 · United States
NIDA NIH HHS · DA007288 · United States
NIDA NIH HHS · T32 DA007288 · United States
NIDA NIH HHS · F32 DA006074 · United States
NIDA NIH HHS · DA-03960 · United States
NIMH NIH HHS · MH-40817 · United States
External Links
PubMed source PMC Full Text View journal details
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