In models of early stage Parkinson's disease (PD), motor deficits are accompanied by excessive activation of striatal glutamate receptors. Group I metabotropic glutamate receptors (mGluRI) play an important, but not well-understood role in PD progression. In mouse brain slices, bath application of the mGluRI agonist DHPG (100mM for 20 min) caused a long-term depression of corticostriatal neurotransmission (LTDDHPG), which was equally reversed by three tested mGluRI antagonists: LY 367385, CPCCOEt, and MPEP. The late phase of LTDDHPG required NO synthesis as it was blocked by the broad spectrum NO synthase (NOS) inhibitor Nw-Nitro-L-arginine (NL-Arg) and impaired in eNOS-deficient mice. Release of cannabinoids (CB) was involved in this form of plasticity as the CB1 receptor antagonist AM251 prevented LTDDHPG, while the CB1 receptor agonist ACEA elicited similar LTD. The NO synthesis necessary for LTDDHPG maintenance was triggered downstream to CB1 receptor since ACEA-evoked LTD was also abolished by NL- Arg. The present findings provide a plausible explanation for the progression of PD via overactivation of mGluRI and the enhanced synthesis of striatal NO, which accelerates degeneration of substantia nigra dopaminergic neurons when entering their endings in the striatum.