TARGETING GROUP III METABOTROPIC GLUTAMATE RECEPTORS IN PARKINSONIAN RATS PRODUCES OPPOSITE BEHAVIORAL EFFECTS IN THE DIRECT AND INDIRECT PATHWAYS OF THE BASAL GANGLIA

Drugs activating group III metabotropic glutamate receptors (mGluRs) represent therapeutic alternatives to L-DOPA (L-3,4- dihydroxyphenylalanine) for the treatment of Parkinson’s disease (PD). Their presynaptic location at GABAergic and glutamatergic synapses within basal ganglia nuclei provide a critical target to reduce abnormal activities associated with PD. The effects of selective group III mGluR agonists (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) and L-(?)-2-amino-4-phosphonobutyric acid (L-AP4) infused into the globus pallidus (GP) or the substantia nigra pars reticulata (SNr) were thus studied in rat models of PD. Bilateral infusions ofACPT-I(1, 2.5,and5nmol/ l) into theGPfully reverse the severe akinetic deficits producedby6-hydroxydopamine nigrostriatal dopamine lesions in a reaction-time task without affecting the performance of controls. Similar results were observed after L-AP4 (1 nmol) or picrotoxin, a GABAA receptor antagonist, infused into the GP. In addition, intrapallidal ACPT-I counteracts haloperidol-induced catalepsy. This effect is reversed by concomitant administration of a selective group III receptor antagonist (RS)- -cyclopropyl-4-phosphonophenylglycine. In contrast, ACPT-I (0.05, 0.1, and 0.25 nmol) infusions into the SNr enhance the lesion- induced akinetic deficits in controlandlesioned ratsanddonot reverse haloperidol-induced catalepsy. L-AP4 (0.05 nmol)andpicrotoxin in the SNr produce the same effects. Together, these results show that activation of group III mGluRs in the GP provides benefits in parkinsonian rats, presumably by modulating GABAergic neurotransmission. The opposite effects produced by group III mGluR acti- vation in the SNr, also observed with a selective mGluR8 agonist, support the use of subtype-selective group III mGluR agonists as a potential antiparkinsonian strategy.