In vivo microdialysis in freely moving rats was used to investigate the presynaptic mechanisms by which LY354740, a novel, potent, selective, and systemically active agonist for group II metabotropic glutamate receptors (mGluRs), alters glutamate neuronal transmission. Basal levels of glutamate and aspartate in striatal dialysates of LY354740 (10 mg/kg i.p.)-treated animals were not significantly different from the saline-treated control animals. In the saline treated controls, veratridine (100 microM) induced a 6-fold increase in glutamate and 9-fold increase in aspartate. However, following LY354740 administration the veratridine-evoked release of glutamate and aspartate was completely prevented. These data demonstrate that LY354740 blocks the evoked release of endogenous excitatory amino acids, and indicate a role for group II mGluRs in presynaptic modulation of glutamate neuronal transmission in vivo. Ireland Ltd.