Effects of Muscarinic Acetylcholine m1 and m4 Receptor Blockade on Dyskinesia in the Hemi-Parkinsonian Rat.

Standard treatment for Parkinson's disease (PD) is L-DOPA, but with chronic administration the majority of patients develop L-DOPA-induced dyskinesia (LID). Emerging evidence implicates the cholinergic system in PD and LID. Muscarinic acetylcholine receptors (mAChR) are known to modulate movement and of late have been implicated as possible targets for LID. Therefore the current study investigated the role of M ₁ and M ₄ mAChRs in LID, on motor performance following L-DOPA treatment, and sought to identify brain sites through which these receptors were acting. We first administered M ₁ R-preferring antagonist trihexyphenidyl (0, 0.1, and 1.0 mg/kg, i.p.) or the M ₄ R-preferring antagonist tropicamide (0, 10, and 30 mg/kg, i.p.) before L-DOPA, after which LID and motor performance were evaluated. Both compounds worsened and extended the time course of LID, while M ₁ R blockade improved motor performance. We then evaluated the effects of tropicamide and trihexyphenidyl on dyskinesia induced by D ₁ R agonist SKF81297 or D ₂ R agonist quinpirole. Surprisingly, both M ₁ R and M ₄ R antagonists reduced D ₁ R agonist-induced dyskinesia but not D ₂ R agonist-induced dyskinesia, suggesting that mAChR blockade differentially affects MSN firing in the absence of postsynaptic DA. Finally, we evaluated effects of striatum- or PPN-targeted tropicamide microinfusion on LID and motor performance. Despite prior evidence, M ₄ R blockade in either site alone did not affect the severity of LID via local striatal or PPN infusions. Taken together, these data suggest M ₄ R as a promising therapeutic target for reducing LID using more selective compounds.
(Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)