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Neuroscience. 2017 Aug 15;357:84-98. doi: 10.1016/j.neuroscience.2017.05.051. Epub 2017 Jun 9.

Alterations of M1 and M4 acetylcholine receptors in the genetically dystonic (dtsz) hamster and moderate antidystonic efficacy of M1 and M4 anticholinergics.

Author information

1
Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Schubertstrasse 81, BFS, 35392 Giessen, Germany. Electronic address: Melanie.Hamann@vetmed.uni-giessen.de.
2
Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universit├Ąt Berlin, Koserstrasse 20, 14195 Berlin, Germany.
3
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, An den Tierkliniken 15, Leipzig, Germany.
4
Neuroimaging Research Section, Centre for Addiction and Mental Health, Toronto, Canada.
5
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, An den Tierkliniken 15, Leipzig, Germany. Electronic address: angelika.richter@vetmed.uni-leipzig.de.

Abstract

Striatal cholinergic dysfunction has been suggested to play a critical role in the pathophysiology of dystonia. In the dtsz hamster, a phenotypic model of paroxysmal dystonia, M1 antagonists exerted moderate antidystonic efficacy after acute systemic administration. In the present study, we examined the effects of the M4 preferring antagonist tropicamid and whether long-term systemic or acute intrastriatal injections of the M1 preferring antagonist trihexyphenidyl are more effective in mutant hamsters. Furthermore, M1 and M4 receptors were analyzed by autoradiography and immunohistochemistry. Tropicamide retarded the onset of dystonic attacks, as previously observed after acute systemic administration of trihexyphenidyl. Combined systemic administration of trihexyphenidyl (30mg/kg) and tropicamide (15mg/kg) reduced the severity in acute trials and delayed the onset of dystonia during long-term treatment. In contrast, acute striatal microinjections of trihexyphenidyl, tropicamid or the positive allosteric M4 receptor modulator VU0152100 did not exert significant effects. Receptor analyses revealed changes of M1 receptors in the dorsomedial striatum, suggesting that the cholinergic system is involved in abnormal striatal plasticity in dtsz hamsters, but the pharmacological data argue against a crucial role on the phenotype in this animal model. However, antidystonic effects of tropicamide after systemic administration point to a novel therapeutic potential of M4 preferring anticholinergics for the treatment of dystonia.

KEYWORDS:

acetylcholine; basal ganglia; movement disorders; muscarinic; striatum

[Indexed for MEDLINE]

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