Group III metabotropic
glutamate (mGlu) receptors are localized in presynaptic terminals within basal ganglia (BG) circuitry that become hyperactive due to
dopamine depletion in
Parkinson's disease (PD). For this reason, group III mGlu receptors, in particular mGlu4, have been considered as key strategic targets for non-dopaminergic pharmacological treatments aimed at modulating these synapses, without producing the well known side-effects of
l-DOPA, in particular the highly disabling
l-DOPA-induced
dyskinesia (LID). Herein we add physiological and functional support to this hypothesis using
Lu AF21934, a novel selective and brain-penetrant mGlu4 receptor positive allosteric modulator (PAM) tool compound. By in vitro electrophysiological recordings we demonstrate that
Lu AF21934 inhibits corticostriatal synaptic transmission and enhances the effect of the orthosteric mGlu4 receptor-preferred agonist
LSP1-2111. In naïve rats,
Lu AF21934 dose-dependently (10 and 30 mg/kg) alleviated
haloperidol-induced
catalepsy. In hemiparkinsonian rats (unilateral
6-hydroxydopamine lesion of the substantia nigra pars compacta),
Lu AF21934 alone did not affect akinesia at the doses tested (10 and 30 mg/kg). However, when
Lu AF21934 was combined with sub-threshold doses of
l-DOPA (1 and 5 mg/kg), it acted synergistically in alleviating akinesia in a dose-dependent manner and, notably, also reduced the incidence of LID but not its severity. Interestingly, these effects occurred at
Lu AF21934 brain free concentrations that showed functional activity in in vitro screens (
calcium flux and electrophysiology assays). These results support the potential for antiparkinsonian clinical use of a combined treatment consisting in
l-DOPA and a mGlu4 receptor PAM to reduce efficacious
l-DOPA doses (generally known as
l-DOPA sparing), while maintaining the same benefit on PD motor troubles, and at the same time minimizing the development of LID. This article is part of a Special Issue entitled '
Metabotropic Glutamate Receptors'.