In models of early stage Parkinson's disease (PD), motor deficits are accompanied by excessive activation of striatal glutamate receptors. Metabotropic glutamate group I receptors (mGluR I) play an important but not well-understood role in PD progression. In mouse brain slices, bath application of the mGluR I agonist (RS)-DHPG (3,5-dihydroxyphenylglycine, 100 microm for 20 min) caused a long-term depression of corticostriatal transmission (LTD(DHPG)), which was reversed by three mGluR I antagonists: LY 367385, CPCCOEt and MPEP. LTD(DHPG) required nitric oxide (NO) synthesis as it was blocked by the broad-spectrum NO synthase (NOS) inhibitor Nomega-nitro-l-arginine (NL-Arg) and impaired under blockade of neuronal NOS and in endothelial NOS-deficient mice. Release of endocannabinoids (eCB) was critically involved in this form of striatal plasticity givem that the CB1 receptor antagonist AM251 prevented LTD(DHPG), while the CB1 agonist ACEA elicited LTD. The NO synthesis necessary for LTD(DHPG) induction occurred downstream of CB1 activation as ACEA-evoked LTD was also abolished by NL-Arg. These findings are relevant for the pathophysiology of PD, as they link the overactivation of group I mGluRs and striatal NO production.

In animal models of early Parkinson's disease (PD), motor deficits are accompanied by excessive striatal glutamate release. Blockade of group I metabotropic glutamate receptors (mGluRs), endocannabinoid degradation and nitric oxide (NO) synthesis combats PD symptoms. Activation of group I mGluRs with the specific agonist 3,5-dihydroxyphenylglycine (DHPG) induces long-term depression of corticostriatal transmission (LTD(DHPG)) in the adult mouse striatum requiring NO synthesis downstream to cannabinoid CB1 receptor (CB1R) activation suggesting a dual role for LTD(DHPG): neuroprotective by down-regulation of glutamatergic transmission and, under certain circumstances, neurotoxic by release of NO. We report now that LTD(DHPG) undergoes a developmental switch from N-methyl-D-aspartate (NMDA)-receptor-dependent/CB1R-independent to NMDA receptor-independent/CB1R-dependent plasticity with NO playing an essential role for LTD(DHPG) at all developmental stages. The gain in function of CB1R is explained by their developmental up-regulation evaluated with real-time reverse transcription-polymerase chain reaction. These findings are relevant for the pathophysiology and therapy of PD as they link the activation of group I mGluRs, endocannabinoid release, and striatal NO production.

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