Objective: To determine the distribution of the glycine transporter 1 (GlyT₁) in brain areas implicated in parkinsonism and L-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease (PD).

Background: L-DOPA‐induced dyskinesia is a common and serious complication of long‐term treatment with L-DOPA affecting nearly 95% of PD patients. We recently demonstrated that inhibition of GlyT₁ with (+)-NFPS, also known as ALX-5407, alleviated dyskinesia and parkinsonism in the marmoset model of PD.

Method: Hemi-parkinsonism was induced in Sprague-Dawley rats by stereotaxic injection of 6-OHDA into the right medial forebrain bundle. The degree of parkinsonism was assessed using the cylinder test and dyskinesia severity was evaluated with the abnormal involuntary movements (AIMs) scale prior to euthanasia. After brain sectioning, we measured GlyT₁ levels in the striatum, globus pallidus, entopeduncular nucleus, subthalamic nucleus, substantia nigra pars reticulata and pars compacta, the motor thalamus, as well as the primary motor cortex, by performing autoradiographic binding using [³H]-NFPS in the presence of ORG-25935 as the cold ligand. Brain sections were selected from 6-OHDA rats exhibiting mild and severe dyskinesia, L-DOPA-naïve 6-OHDA rats and sham-lesioned animals.

Results: In the lesioned hemisphere, [³H]-NFPS binding levels were significantly increased in the subthalamic nucleus of L-DOPA-treated, non-dyskinetic 6-OHDA-lesioned rats compared to L-DOPA-naïve 6-OHDA-lesioned animals (2.20-fold, P < 0.05). [³H]-NFPS binding levels were also increased in the globus pallidus and thalamus of dyskinetic rats compared to non-dyskinetic L-DOPA-treated 6-OHDA-lesioned rats (by 51% and 99%, P < 0.05 and 0.01, respectively). No significant differences in [³H]-NFPS binding levels were observed in the other brain areas.

Conclusion: Our findings indicate that GlyT₁ inhibition may act in the globus pallidus and the thalamus to diminish dyskinesia in PD. On the other hand, administration of L-DOPA appears to be associated with increased GlyT₁ levels in the subthalamic nucleus. Further studies are warranted to shed light on the mechanisms and circuitry underlying GlyT₁ involvement in PD and dyskinesia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/determination-of-glycine-transporter-1-levels-with-3h-nfps-binding-in-hemi-parkinsonian-rats-with-l-dopa-induced-dyskinesia/