Objective: To determine the role of M4 muscarinic receptors in the expression of L-DOPA-induced dyskinesia (LID) and dystonia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets.

Background: Selective antagonism of muscarinic M4 receptors has been proposed to be a target for relieving motor symptoms of Parkinson’s disease or dystonia with reduced peripheral side effects. To investigate this, we studied the effects of clinically used anticholinergics and a novel selective M4 antagonist, NBI-675, on L-DOPA-induced increase in locomotor activity, reversal of motor disability and induction of dyskinesia in MPTP-treated common marmosets.

Methods: MPTP-treated, L-DOPA-primed adult common marmosets (n=6-8) were pre-treated with trihexyphenidyl (0.5 & 1 mg/kg po), benztropine (0.25 & 0.5 mg/kg sc), scopolamine (0.1 & 0.3 mg/kg sc), methylscopolamine (0.1 & 0.3 mg/kg sc) and NBI-675 (1, 3 & 7.5 mg/kg po; kindly provided by Neurocrine Biosciences Inc.) or their vehicles. L-DOPA (8 mg/kg + benserazide, 10 mg/kg po) or vehicle was administered 1h later. Drug treatments were administered in a randomised manner. Locomotor activity was assessed using automated activity cages fitted with photocells. Motor disability and dyskinesia was visually scored using established rating scales by raters blinded to the treatment. Data were analysed by Friedman’s followed by post hoc Dunn’s test (GraphPad Prism).

Results: Co-administration of clinically used centrally-acting anticholinergics (trihexyphenidyl, benztropine and scopolamine) in combination with L-DOPA resulted in improvement of locomotor activity and motor disability but enhanced expression of dyskinesia. Peripherally acting methylscopolamine, as expected, showed no effect. The M4-selective antagonist, NBI-675, had no significant effect on L-DOPA-induced improvement of locomotor activity and reversal of motor disability, although duration of effect was extended. In addition, LID was enhanced and, in general, combination of both drugs resulted in higher expression of dystonia than chorea.

Conclusions: Improvement in motor deficits by anticholinergics does not appear to be mediated by M4 muscarinic receptors, however, these receptors are involved in the expression of LID, and particularly the expression of dystonia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/selective-m4-antagonism-potentiates-l-dopa-induced-dyskinesia-in-mptp-treated-common-marmosets/