The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in the normal motor function, as well as in pathological conditions such as Parkinson's disease. Development of a complete understanding of the role of the STN in motor control will require a detailed understanding of the mechanisms involved in the regulation of excitatory and inhibitory synaptic transmission in this nucleus. Here, we report that activation of groups I or III metabotropic glutamate (mGlu) receptors, but not group II, causes a depression of excitatory transmission in the STN. In contrast, mGlu receptor activation has no effect on the inhibitory transmission in this nucleus. Further characterization of the group I mGlu receptor-induced effect on EPSCs suggests that this response is mediated by mGlu1 and not mGlu5. Further, paired pulse studies suggest that both the mGlu1 receptor and the group III mGlu receptor-mediated effects are due to a presynaptic mechanism. If these receptors are involved in endogenous synaptic transmission in the STN, these results raise the exciting possibility that selective agents targeting mGlu receptors may provide a novel approach for the treatment of motor disorders involving the STN.