Co‐localization and functional interaction between adenosine A_2A and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum

<jats:title>Abstract</jats:title><jats:p>The anti‐Parkinsonian effect of glutamate metabotropic group 5 (mGluR5) and adenosine A<jats:sub>2A</jats:sub> receptor antagonists is believed to result from their ability to postsynaptically control the responsiveness of the indirect pathway that is hyperfunctioning in Parkinson's disease. mGluR5 and A<jats:sub>2A</jats:sub> antagonists are also neuroprotective in brain injury models involving glutamate excitotoxicity. Thus, we hypothesized that the anti‐Parkinsonian and neuroprotective effects of A<jats:sub>2A</jats:sub> and mGluR5 receptors might be related to their control of striatal glutamate release that actually triggers the indirect pathway. The A<jats:sub>2A</jats:sub> agonist, CGS21680 (1–30 n<jats:sc>m</jats:sc>) facilitated glutamate release from striatal nerve terminals up to 57%, an effect prevented by the A<jats:sub>2A</jats:sub> antagonist, SCH58261 (50 n<jats:sc>m</jats:sc>). The mGluR5 agonist, CHPG (300–600 μ<jats:sc>m</jats:sc>) also facilitated glutamate release up to 29%, an effect prevented by the mGluR5 antagonist, MPEP (10 μ<jats:sc>m</jats:sc>). Both mGluR5 and A<jats:sub>2A</jats:sub> receptors were located in the active zone and 57 ± 6% of striatal glutamatergic nerve terminals possessed both A<jats:sub>2A</jats:sub> and mGluR5 receptors, suggesting a presynaptic functional interaction. Indeed, submaximal concentrations of CGS21680 (1 n<jats:sc>m</jats:sc>) and CHPG (100 μ<jats:sc>m</jats:sc>) synergistically facilitated glutamate release and the facilitation of glutamate release by 10 n<jats:sc>m</jats:sc> CGS21680 was prevented by 10 μ<jats:sc>m</jats:sc> MPEP, whereas facilitation by 300 μ<jats:sc>m</jats:sc> CHPG was prevented by 10 n<jats:sc>m</jats:sc> SCH58261. These results provide the first direct evidence that A<jats:sub>2A</jats:sub> and mGluR5 receptors are co‐located in more than half of the striatal glutamatergic terminals where they facilitate glutamate release in a synergistic manner. This emphasizes the role of the modulation of glutamate release as a likely mechanism of action of these receptors both in striatal neuroprotection and in Parkinson's disease.</jats:p>