Objective: To investigate the difference in results according to the mode of levodopa administration and the effect of zonisamide (ZNS) on striatal cholinergic system, we analyzed the mRNA expression of striatal acetylcholine receptors in a rat model of Parkinson’s disease (PD) in relation to the development of levodopa-induced dyskinesia (LID).

Background: Striatal cholinergic interneurons strongly influence motor function and basal ganglia output. We have previously reported [1] that intermittent levodopa treatment on unilateral PD model rats developed LID, and striatal adenosine A2A receptor mRNA expression was elevated. However, co-administration of ZNS ameliorated the development of LID and inhibited up-regulation of A2A receptors.

Method: Unilateral PD model rats were made by stereotaxic injection of 6-OHDA into the unilateral medial forebrain bundle. These rats were subdivided into four groups and treated as follows; 1) no medication (group N), 2) continuous levodopa infusion (group C), 3) intermittent levodopa injection (group I), 4) intermittent levodopa and ZNS injection (group Z). Two weeks after the treatment, the severity of LID was evaluated, and the expression of striatal mRNAs for muscarinic M1 (Chrm1) and M4 (Chrm1) receptors and nicotinic alpha 7 (Chrna7) and beta 2 (Chrnb2) subunits were analyzed by real-time RT-PCR.

Results: LID was not observed in group C, but was found in group I. Group Z also developed LID, but the dyskinesia in it was less severe than that in group I. Expression of mRNAs for Chrm1, Chrm4, Chrna7 and Chrnb2 was not changed in group N, C, and I. On the other hand, expression of mRNAs for these cholinergic receptors were all reduced in group Z.

Conclusion: ZNS may ameliorate LID through decreasing mRNAs for striatal cholinergic receptors.

References: [1] Oki M, Kaneko S, Morise S, Takenouchi N, Hashizume T, Tsuge A, Nakamura M, Wate R, Kusaka H. Zonisamide ameliorates levodopa-induced dyskinesia and reduces expression of striatal genes in Parkinson model rats. Neurosci Res 122:45-50, 2017

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MDS Abstracts - https://www.mdsabstracts.org/abstract/zonisamide-ameliorates-levodopa-induced-dyskinesia-via-striatal-cholinergic-system-in-a-rat-model-of-parkinsons-disease/