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L-3,4-dihydroxyphenylalanine (L-DOPA) remains the main treatment for motor symptoms of Parkinson's disease (PD). However, chronic use is associated with the development of complications such as L-DOPA-induced dyskinesia. We previously demonstrated that LY-487,379, a highly selective metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulator (PAM), reduces the severity of L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, without interfering with the anti-parkinsonian action of L-DOPA. Here, we seek to determine the effect of AZD8529, another highly selective mGluR2 PAM, on L-DOPA-induced AIMs in the 6-OHDA-lesioned rat. Unlike LY-487,379, AZD8529 has previously undergone clinical trials and could therefore be repurposed if proven efficacious in pre-clinical studies. We first determined the pharmacokinetic (PK) profile of AZD8529 to administer doses leading to clinically relevant plasma levels in the behavioural studies. Then, dyskinetic 6-OHDAlesioned rats were administered AZD8529 (0.1, 0.3, and 1 mg/kg) or vehicle in combination with L-DOPA followed by assessment of AIMs severity. The cylinder test was then used to evaluate the effect of AZD8529 on the anti-parkinsonian action of L-DOPA. We found that AZD8529 (0.1, 0.3 and 1 mg/kg) in combination with L-DOPA significantly reduced the severity of AIMs duration (P < 0.05), but not amplitude, when compared to L-DOPA/vehicle. AZD8529 administration did not interfere with L-DOPA anti-parkinsonian action. Our results provide evidence that mGluR2 positive allosteric modulation with AZD8529 may be a viable, yet relatively modest, treatment strategy to alleviate L-DOPA-induced., Competing Interests: Declarations. Ethics approval: This study was approved by the ethics committee of McGill University and the Montreal Neurological Institute-Hospital (The Neuro, Animal Use Protocol 2017–7922) in accordance with the regulations defined by the Canadian Council on Animal Care. Consent to participate: Not applicable. Consent to publish: Not applicable. Competing interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Bitopertin, a selective glycine transporter 1 (GlyT 1 ) inhibitor, has been extensively studied for the treatment of schizophrenia, with known safety and tolerability profiles in the clinic. Whereas several rodent experiments have been reported, the pharmacokinetic (PK) profile of bitopertin in rodents has not been extensively reported, as only two studies disclosed limited PK parameters in male rats after oral administration. Here, we determined the PK profile of bitopertin in female Sprague-Dawley rats. Blood samples were taken serially, before and after sub-cutaneous (0.03, 0.1, 0.3, 1, and 3 mg/kg) or intra-venous (0.1 mg/kg) administration. Plasma levels were determined by high-performance liquid chromatography coupled with heat-assisted electrospray ionisation tandem mass spectrometry (HPLC-HESI MS/MS). Subsequently, PK parameters were calculated using non-compartmental analysis, including area under the curve (AUC), time (T max ) to maximal plasma concentration (C max ), clearance (CL), volume of distribution (V z ), as well as half-life (T 1/2 ). Following sub-cutaneous injection, bitopertin exhibited dose-dependent AUC 0-∞ (439.6-34,018.9 ng/mL) and T max (3.7-24.0 h), a very long terminal T 1/2 (35.06-110.32 h) and low CL (0.07-0.13 L/h/kg), suggesting that bitopertin is slowly absorbed and eliminated in the rat. The observed relationship between dose and the extent of drug exposure (AUC) was linear. Following administration of all sub-cutaneous doses, measured bitopertin plasma levels were comparable to levels achieved with doses already administered in the clinic. We hope that our results will be useful in the design of pre-clinical experiments in which this drug will eventually be administered sub-cutaneously., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Dyskinesia remains an unmet need in Parkinson's disease (PD). We have previously demonstrated that glycine transporter 1 (GlyT1) inhibition with ALX-5407 reduces dyskinesia and slightly improves parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to determine the effect of bitopertin, a clinically-tested GlyT1 inhibitor, on parkinsonism and dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat. To do so, we assessed the effect of bitopertin on parkinsonism as monotherapy and as adjunct to a low dose of L-3,4-dihydroxyphenylalanine (L-DOPA). We then assessed the efficacy of bitopertin on dyskinesia in the context of acute challenge and chronic administration studies. Lastly, we evaluated whether de novo treatment with bitopertin, started concurrently with L-DOPA, would diminish the development of dyskinesia. We discovered that bitopertin (0.3 mg/kg), when administered alone, reduced the severity of parkinsonism by 35% (P < 0.01). As adjunct to a low dose of L-DOPA, bitopertin (3 mg/kg) enhanced the anti-parkinsonian effect of L-DOPA by 36% (P < 0.05). Moreover, the acute addition of bitopertin (0.03 mg/kg) to L-DOPA reduced dyskinesia by 27% (P < 0.001), and there was no tolerance to the anti-dyskinetic benefit after 4 weeks of daily administration. Lastly, bitopertin (0.03 mg/kg) started concurrently with L-DOPA, also attenuated the development of dyskinesia, by 33% (P < 0.01), when compared to L-DOPA alone. Our results suggest that GlyT1 inhibition may simultaneously reduce parkinsonism and L-DOPA-induced dyskinesia and represents a novel approach to treat, possibly prevent, motor complications in PD., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective therapy for motor symptoms of Parkinson's disease (PD); however, with repeated administration, as many as 94% of PD patients develop complications such as L-DOPA-induced dyskinesia. We previously demonstrated that EMD-281,014, a highly selective serotonin 2A (5-HT 2A ) receptor antagonist, reduces the severity of dyskinesia in the parkinsonian marmoset, without interfering with L-DOPA anti-parkinsonian benefit. Here, we assessed the effects of EMD-281,014 on L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat. We first determined the pharmacokinetic profile of EMD-281,014, to administer doses leading to clinically relevant plasma levels in the behavioural experiments. Dyskinetic 6-OHDA-lesioned rats were then administered EMD-281,014 (0.01, 0.03 and 0.1 mg/kg) or vehicle in combination with L-DOPA and AIMs severity was evaluated. We also assessed the effect of EMD-281,014 on L-DOPA anti-parkinsonian action with the cylinder test. We found that the addition of EMD-281,014 (0.01, 0.03 and 0.1 mg/kg) to L-DOPA did not reduce AIMs severity (P > 0.05), when compared to vehicle. EMD-281,014 did not compromise L-DOPA anti-parkinsonian action. Our results suggest that the highly selective 5-HT 2A receptor antagonist EMD-281,014 is well-tolerated by parkinsonian rats, but does not attenuate L-DOPA-induced AIMs. Our results highlight differences between rodent and primate models of PD when it comes to determining the anti-dyskinetic action of 5-HT 2A receptor antagonists.