Blockade of excitatory amino acid transporters in the rat hippocampus results in enhanced activation of group I and group III metabotropic glutamate receptors

The idea that excitatory amino acid transporters (EAATs) can control the activation of specific metabotropic glutamate receptors (mGluRs) was investigated in rat hippocampal slices. Using the accumulation of inositol phosphates as a measure of group I mGluR activity, we have shown that the broad spectrum, non-transportable EAAT blocker, TBOA, produces a significant shift to the left of agonist concentration–response curves. Moreover, this increase in potency did not occur if endogenous glutamate was enzymatically removed, suggesting a glutamate-dependent mechanism. This shift in potency was shown to be NMDA and group II mGlu receptor independent. Additionally, experiments with selective antagonists indicated that the group I receptor responsible for the stimulation of inositol phosphate production in this preparation is likely to be mGluR5. Inhibition of forskolin-stimulated cyclic AMP (cAMP) production was used as an index of group II/III mGluR activity. TBOA produced a rightward shift of the forskolin concentration–response curve. A group III, but not a group II, mGluR agonist also produced this effect, suggesting that the TBOA-mediated increase in glutamate activates a receptor, which appears to be a member of the group III mGluR subset. This was confirmed by the observation that an antagonist of group III mGluRs, prevented the TBOA-induced rightward shift in forskolin potency. These results provide evidence of a role for EAATs in the regulation of mGluR5 and group III mGluRs in the rat hippocampus, which may have therapeutic implications.