Presynaptic mGlu2/3 autoreceptors exist in rat spinal cord nerve terminals as suggested by the finding that LY379268 inhibited the 15 mM KCl-evoked release of [H]D-aspartate ([H]D-Asp) in a LY341495-sensitive manner. Spinal cord glutamatergic nerve terminals also possess presynaptic release-regulating 5-HT heteroreceptors. Actually, the 15 mM KCl-evoked [H]D-Asp exocytosis from spinal cord synaptosomes was reduced by the 5-HT agonist (±)DOI, an effect reversed by the 5-HT antagonists MDL11,939, MDL100907, ketanserin and trazodone (TZD). We investigated whether mGlu2/3 and 5-HT receptors colocalize and cross-talk in these terminals and if 5-HT ligands modulate the mGlu2/3-mediated control of glutamate exocytosis. Western blot analysis and confocal microscopy highlighted the presence of mGlu2/3 and 5-HT receptor proteins in spinal cord VGLUT1 positive synaptosomes, where mGlu2/3 and 5-HT receptor immunoreactivities largely colocalize. Furthermore, mGlu2/3 immunoprecipitates from spinal cord synaptosomes were also 5-HT immunopositive. Interestingly, the 100 pM LY379268-induced reduction of the 15 mM KCl-evoked [H]D-Asp overflow as well as its inhibition by 100 nM (±)DOI became undetectable when the two agonists were concomitantly added. Conversely, 5-HT antagonists (MDL11,939, MDL100907, ketanserin and TZD) reinforced the release-regulating activity of mGlu2/3 autoreceptors. Increased expression of mGlu2/3 receptor proteins in synaptosomal plasmamembranes paralleled the gain of function of the mGlu2/3 autoreceptors elicited by 5-HT antagonists. Based on these results, we propose that in spinal cord glutamatergic terminals i) mGlu2/3 and 5-HT receptors colocalize and interact one each other in an antagonist-like manner, ii) 5-HT antagonists are indirect positive allosteric modulator of mGlu2/3 autoreceptors controlling glutamate exocytosis.
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