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In previous experiments, we have discovered that positive allosteric modulation of metabotropic glutamate 2 (mGlu 2 ) receptors enhances the anti-parkinsonian action of an optimal dose of L-3,4-dihydroxyphenylalanine (L-DOPA). Whether selective mGlu 2 positive allosteric modulation would also alleviate parkinsonian disability as monotherapy or as adjunct to a sub-optimal dose of L-DOPA has not been determined. Here, we assessed the anti-parkinsonian effect of mGlu 2 positive allosteric modulation as monotherapy and adjunct to a sub-optimal dose of L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets. The highly selective positive allosteric modulator (PAM) LY-487,379 was utilised to activate mGlu 2 receptors. When administered as monotherapy, LY-487,379 10 mg/kg diminished global parkinsonism by 48% (P < 0.001) and increased duration of on-time by 7-fold, when compared to vehicle treatment (P < 0.05). When added to a sub-optimal dose of L-DOPA, LY-487,379 10 mg/kg decreased global parkinsonism by 44% (P < 0.001) and extended duration of on-time by 2.5-fold (P < 0.01). Our results indicate that selective mGlu 2 positive allosteric modulation elicits anti-parkinsonian benefits as monotherapy and as adjunct to sub-optimal dose of L-DOPA paradigms, potentially suggesting that mGlu 2 PAMs may have a therapeutic niche early in the treatment of PD as DOPA-sparing agents., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The common marmoset has emerged as a popular model in neuroscience research, in part due to its reproductive efficiency, genetic and neuroanatomical similarities to humans and the successful generation of transgenic lines. Stereotaxic procedures in marmosets are guided by 2D stereotaxic atlases, which are constructed with a limited number of animals and fail to account for inter-individual variability in skull and brain size. Here, we developed a frameless imaging-guided stereotaxic system that improves upon traditional approaches by using subject-specific registration of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) data to identify a surgical target, namely the putamen, in two marmosets. The skull surface was laser-scanned to create a point cloud that was registered to the 3D reconstruction of the skull from CT. Reconstruction of the skull, as well as of the brain from MR images, was crucial for surgical planning. Localisation and injection into the putamen was done using a 6-axis robotic arm controlled by a surgical navigation software (Brainsight™). Integration of subject-specific registration and frameless stereotaxic navigation allowed target localisation specific to each animal. Injection of alpha-synuclein fibrils into the putamen triggered progressive neurodegeneration of the nigro-striatal system, a key feature of Parkinson's disease. Four months post-surgery, a PET scan found evidence of nigro-striatal denervation, supporting accurate targeting of the putamen during co-registration and subsequent surgery. Our results suggest that this approach, coupled with frameless stereotaxic neuronavigation, is accurate in localising surgical targets and can be used to assess endpoints for longitudinal studies., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Dyskinesia and psychosis are complications encountered in advanced Parkinson's disease (PD) following long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA). Disturbances in the glutamatergic system have been associated with both dyskinesia and psychosis, making glutamatergic modulation a potential therapeutic approach for these. Treatments thus far have sought to dampen glutamatergic transmission, for example through blockade of N-methyl-D-aspartate (NMDA) receptors or modulation of metabotropic glutamate receptors 5. In contrast, activation of the glycine-binding site on NMDA receptors is required for their physiological response. Here, we investigated whether indirectly enhancing glutamatergic transmission through inhibition of glycine re-uptake would be efficacious in diminishing both dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. Six marmosets were rendered parkinsonian by MPTP injection. Following repeated administration of L-DOPA to induce dyskinesia and PLBs, they underwent acute challenges of the glycine transporter 1 (GlyT 1 ) inhibitor ALX-5407 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA, after which the severity of dyskinesia, PLBs and parkinsonian disability was evaluated. In combination with L-DOPA, ALX-5407 0.1 and 1 mg/kg significantly reduced the severity of dyskinesia, by 51% and 41% (both P < 0.001), when compared to vehicle. ALX-5407 0.01, 0.1 and 1 mg/kg also decreased the severity of global PLBs, by 25%, 51% and 38% (all P < 0.001), when compared to vehicle. The benefits on dyskinesia and PLBs were achieved without compromising the therapeutic effect of L-DOPA on parkinsonism. Our results suggest that GlyT 1 inhibition may be a novel strategy to attenuate dyskinesia and PLBs in PD, without interfering with L-DOPA anti-parkinsonian action., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Psychosis and dyskinesia significantly diminish the quality of life of patients with advanced Parkinson's disease (PD). Available treatment options are unfortunately few and their use is limited by adverse effects. We have recently shown that activation of metabotropic glutamate 2 and 3 (mGlu2/3) receptors produced significant relief of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced psychosis-like behaviours (PLBs) and dyskinesia in experimental models of PD. Here, using the highly-selective mGlu2 positive allosteric modulator (PAM) LY-487,379, we seek to determine the contribution of selective mGlu2 activation on both L-DOPA-induced PLBs and dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We first determined the pharmacokinetic (PK) profile of LY-487,379 in the common marmoset, following which we administered it (0.1, 1 and 10 mg/kg) or its vehicle to 6 MPTP-lesioned marmosets previously exposed to L-DOPA to elicit stable PLBs and dyskinesia. We found that LY-487,379 provided a ≈45% reduction of the global PLBs observed and reduced global dyskinesia score by ≈ 55%. Moreover, LY-487,379 enhanced the anti-parkinsonian effect of L-DOPA, by reducing global parkinsonian score by ≈ 15%. Our data suggest that selective mGlu2 positive allosteric modulation with LY-487,379 may represent a potential therapeutic approach to alleviate both L-DOPA-induced PLBs and dyskinesia in PD., (Copyright © 2020 Elsevier B.V. All rights reserved.)