Objective: To determine the effect of positive allosteric modulation of the metabotropic glutamate type 2 (mGlu2) receptor in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset using a low dose L-3,4-dihydroxyphenylalanine (L-DOPA) paradigm.

Background: Activation of mGlu2 receptors dampens glutamate release in cortico-striatal synapses, which may alleviate the abnormal glutamatergic transmission that occurs in Parkinson’s disease (PD). Indeed, we demonstrated that mGlu2 receptor activation enhances the anti-parkinsonian action of a therapeutic dose of L-DOPA. However, it is unclear whether this benefit extends to a low dose L-DOPA paradigm that sub-optimally reduces parkinsonism. To this end, we administered the mGlu2 positive allosteric modulator (PAM) biphenylindanone (BINA) to MPTP-lesioned marmosets and assessed its effects on parkinsonism, dyskinesia, and psychosis-like behaviours (PLBs).

Method: Six common marmosets (Callithrix jacchus, 3F and 3M) were rendered parkinsonian by MPTP injection. In a within-subjects design, animals were administered L-DOPA/benserazide 7.5/1.875 mg/kg in combination with BINA (vehicle, 0.1, 1, and 10 mg/kg). The severity of parkinsonism, dyskinesia, and PLBs was assessed post hoc.

Results: When BINA 1 and 10 mg/kg were added to L-DOPA, global parkinsonism severity was reduced by 38% (P < 0.0001) and 53% (P < 0.001). This effect was accompanied by a 52% and 60% increase in on-time (both P < 0.001). Whereas the combination of BINA 10 mg/kg and L-DOPA led to a 94% and 93% reduction in global dyskinesia and PLBs severity (both P < 0.01), lower doses failed to achieve statistical significance.

Conclusion: Our results suggest that mGlu2 positive allosteric modulation may enhance the anti-parkinsonian benefit conferred by low dose L-DOPA. Compounds with this activity may be useful in an L-DOPA-sparing strategy that attempts to provide long-term control of symptoms and quality of life for early stage PD patients.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-mglu2-positive-allosteric-modulator-bina-extends-enhances-low-dose-l-dopa-anti-parkinsonian-action-in-the-mptp-lesioned-marmoset/