Objective: To evaluate if, upon chronic administration, tolerance to the anti-dyskinetic effect of the glycine transporter 1 (GlyT₁) inhibitor bitopertin, would develop, in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease (PD).

Background: L-3,4-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for PD, despite causing dyskinesia, a debilitating complication. New treatment options are needed to address dyskinesia. We have previously reported that bitopertin, a GlyT₁ inhibitor that has undergone extensive clinical evaluation of psychiatric conditions, reduced established dyskinesia in the 6-OHDA-lesioned rat.

Method: Hemi-parkinsonism was induced by stereotaxic injection of 6-OHDA into the right medial forebrain bundle of Sprague-Dawley rats. The degree of parkinsonism was assessed using the cylinder test. Following a dyskinesia induction period, rats with constant and reproducible dyskinesia were administered bitopertin (0.03 or 0.3 mg/kg s.c) or vehicle once daily, in combination with L-DOPA and the severity of axial, limbs and orolingual (ALO) abnormal involuntary movements (AIMs) was rated on day 1, 8, 15, 22 and 29.

Results: Chronic administration of bitopertin 0.3 mg/kg led to a significant reduction of integrated ALO AIMs severity by 62% (P < 0.01), whereas L-DOPA/bitopertin 0.03 mg/kg did not reach significance when compared to L-DOPA/vehicle on day 29. When compared to day 1, integrated ALO AIMs severity was reduced when L-DOPA/bitopertin 0.03 and 0.3 mg/kg were combined with L-DOPA, by 52% (P < 0.0001) and 26% (P < 0.05), respectively.

Conclusion: Our results indicate that no tolerance to the anti-dyskinetic effect of GlyT₁ inhibition with bitopertin develops upon chronic administration. From a translational perspective, these results suggest that bitopertin would maintain its efficacy over the long term, if administered to dyskinetic PD patients. Considering the extensive clinical characterisation of bitopertin, it might be repurposed relatively quickly for the treatment of L-DOPA-induced dyskinesia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/chronic-administration-of-bitopertin-a-glyt1-inhibitor-in-the-dyskinetic-6-ohda-lesioned-rat-model-of-parkinsons-disease/