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

Research paper by Nicole E NE Chambers, Samantha M SM Meadows, Anne A Taylor, Eitan E Sheena, Kathryn K Lanza, Melissa M MM Conti, Christopher C Bishop

Indexed on: 07 Sep '19Published on: 29 Apr '19Published in: Neuroscience



Abstract

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 and M 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 MR-preferring antagonist trihexyphenidyl (0, 0.1, and 1.0 mg/kg, i.p.) or the MR-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 MR blockade improved motor performance. We then evaluated the effects of tropicamide and trihexyphenidyl on dyskinesia induced by DR agonist SKF81297 or DR agonist quinpirole. Surprisingly, both MR and MR antagonists reduced DR agonist-induced dyskinesia but not DR 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, MR blockade in either site alone did not affect the severity of LID via local striatal or PPN infusions. Taken together, these data suggest MR as a promising therapeutic target for reducing LID using more selective compounds. Copyright © 2019. Published by Elsevier Ltd.