Targeting group III metabotropic glutamate receptors produces complex behavioral effects in rodent models of Parkinson's disease

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 of ACPT- I ( 1, 2.5, and 5 nmol/mu l) into the GP fully reverse the severe akinetic deficits produced by 6- 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 GABA(A) 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)- alpha-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 control and lesioned rats and do not reverse haloperidol- induced catalepsy. L- AP4 ( 0.05 nmol) and picrotoxin 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 activation 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.