Effects of Muscarinic Acetylcholine m1 and m4 Receptor Blockade on Dyskinesia in the Hemi-Parkinsonian Rat. (15th June 2019)

• Record Type: Journal Article
• Authors: Chambers, Nicole E.; Meadows, Samantha M.; Taylor, Anne; Sheena, Eitan; Lanza, Kathryn; Conti, Melissa M.; Bishop, Christopher
• Is Part Of: Neuroscience. Volume 409(2019)
• Page Start: 180
• Page End: 194
• Publication Date: 2019-06-15
• Subjects: 6-OHDA 6-hydroxydopamine -- ACh Acetylcholine -- AIMs Abnormal involuntary movements -- ALO Axial, limb, and orolingual -- ChI Cholinergic interneuron -- D1R Dopamine D1 receptor -- D2R Dopamine D2 receptor -- DA Dopamine -- DOPAC 3, 4-dihydroxyphenylacetic acid -- FAS Forepaw adjusting steps -- GABA γ-aminobutyric acid -- HPLC-ED High performance liquid chromatography, electrochemical detection -- LID L-DOPA-induced dyskinesia -- M1R M1 muscarinic acetylcholine receptor -- M4R M4 muscarinic acetylcholine receptor -- mAChR Muscarinic acetylcholine receptor -- MSN Medium Spiny Neuron -- PD Parkinson's disease -- PPN Pedunculopontine tegmental nucleus -- STN Subthalamic nucleus; cholinergic -- dopamine -- striatum -- pedunculopontine nucleus -- Parkinson's disease -- L-DOPA; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2019.04.008
• Languages: English
• ISSNs: 0306-4522

Abstract

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 M1 and M4 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 M1 R-preferring antagonist trihexyphenidyl (0, 0.1, and 1.0 mg/kg, i.p.) or the M4 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 M1 R blockade improved motor performance. We then evaluated the effects of tropicamide and trihexyphenidyl on dyskinesia induced by D1 R agonist SKF81297 or D2 R agonist quinpirole. Surprisingly, both M1 R and M4 R antagonists reduced D1 R agonist-induced dyskinesia but not D2 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, M4 R blockade in either site alone did not affect the severity of LID via local striatal or PPN infusions. Taken together, these data suggest M4 R as a promising therapeutic target for reducing LID using more selective compounds. Highlights: Muscarinic M1 R or M4 R antagonists modulate LID and DA-agonist-induced dyskinesia. L-DOPA's motor efficacy is enhanced by M1 R but not M4 R blockade. Exacerbation of LID by mAChR blockade may be conferred by both pre- and post-synaptic mechanisms.