The Origin and Neuronal Function ofIn VivoNonsynaptic Glutamate

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.

Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

“…In addition to the regulation of glutamate release, NAC, via GSH or its derivatives, has the capacity to modulate NMDA activity (Gilbert et al 1991;Leslie et al 1992;Varga et al 1997). NAC regulation of the cystine/glutamate antiporter and mGluR2/3, as described above, can also regulate dopamine release from presynaptic terminals (Baker et al 2002). NAC may also regulate dopamine release via the modulation of the redox status of the cell, via antioxidant effects of GSH and L-cysteine (JanÄky et al 2007; Gere-Paszti and Jakus 2009).…”

Homer Isoforms Differentially Regulate Cocaine-Induced Neuroplasticity

“…The cystine-glutamate exchanger is the primary source of accumbens extracellular glutamate in vivo (Baker et al, 2002) and cocaine-induced downregulation of cystineglutamate exchange underlies the alterations in extracellular levels of glutamate and glutamate releasability observed following withdrawal from either contingent or noncontingent cocaine administration (Baker et al, 2003). Although it still remains to be determined precisely how Homer proteins interact with the cystine-glutamate exchanger or how postsynaptic scaffolding proteins influence presynaptic glutamate release, our finding that preventing the cocaineinduced reduction in long Homer isoforms reversed the effects of cocaine withdrawal upon extracellular glutamate content and glutamate releasability, points to a potential interaction between Homer and the cystine/glutamate exchanger in the expression of cocaine-induced glutamate neural pathologies relevant to addiction.…”

Rapid Synaptic Plasticity of Glutamatergic Synapses on Dopamine Neurons in the Ventral Tegmental Area in Response to Acute Amphetamine Injection

“…Nonvesicular glutamate may be another potential source of glutamate that could contribute to potentiation. Psychostimulants promote glutamate efflux in the VTA (Kalivas and Duffy, 1995;Xue et al, 1996;Wolf and Xue, 1998), due to efflux from glutamate transporters and cystine-glutamate exchangers (Wolf and Xue 1999;Baker et al, 2002Baker et al, , 2003. In principle, this rise in extracellular glutamate could contribute to the development of LTP, but studies indicate that this rise does not begin until 2 h after psychostimulant exposure (Xue et al, 1996;Wolf and Xue, 1998).…”