P9 oppositeeffectsofgroup iiimetabotropic glutamatereceptorsactivation intheglobus pallidusorthesubstantianigraparsreticulata in regulatingmotorcontrol inparkinsonianrats

Metabotropic glutamate receptors (mGluRs) expressed in the basal ganglia have been identified as a possible target for Parkinson’s disease (PD) treatment. Group III mGluRs are highly expressed presynaptically on subthalamonigral and striatopallidal neurons that are hyperactive in parkinsonian state. The selective group III mGluRs agonist, 1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I), has been used to modulate Glu and/or GABA transmission by a presynaptic activation of mGluRs located on these pathways. The behavioral effects produced by ACPT-I locally infused in the substantia nigra reticulata (SNr) or in the globus pallidus (GP) were investigated in animal models of PD. Striatal dopamine denervation produced severe akinetic deficits in animals performing an operant reaction time (RT) task. ACPT-I (0.05, 0.1, 0.25 nmol/mL) bilaterally infused in the SNr potentiated the lesion-induced akinesia (e.g. increased delayed responses and RTs) in 6-OHDA-lesioned rats and prevented the animals from performing the task at higher doses (above 1 nmol/mL). In contrary, low doses of ACPT-I infused in the GP (0.1 to 0.3 nmol/mL) had no effect, while higher doses (1 to 5 nmol/mL) totally reversed the lesion-induced deficits without affecting performance of sham animals. In addition, ACPT-I in the GP reduced haloperidolinduced catalepsy and enhanced apomorphine-induced circling in unilateral 6-OHDA lesioned rats. Similar results were observed with the GABA-A agonist picrotoxin (0.16 nmol/mL) infused into the GP. Altogether, these results show that group III mGluRs activation in SNr, either by reducing GABA activity and/or by increasing glutamate release, enhance the inhibitory control of basal ganglia outflow and contribute to worsen the parkinsonian symptoms. In contrary, activating these receptors in the GP provide motor benefits in animal models of PD, presumably by decreasing the hyperactive GABAergic striatopallidal pathway.