Attenuated dopaminergic neurodegeneration and motor dysfunction in hemiparkinsonian mice lacking the alpha 5 nicotinic acetylcholine receptor subunit

Show full item record



Permalink

http://hdl.handle.net/10138/253492

Citation

Leino , S , Koski , S K , Hänninen , R , Tapanainen , T , Rannanpää , S & Salminen , O 2018 , ' Attenuated dopaminergic neurodegeneration and motor dysfunction in hemiparkinsonian mice lacking the alpha 5 nicotinic acetylcholine receptor subunit ' , Neuropharmacology , vol. 138 , pp. 371-380 . https://doi.org/10.1016/j.neuropharm.2018.06.028

Title: Attenuated dopaminergic neurodegeneration and motor dysfunction in hemiparkinsonian mice lacking the alpha 5 nicotinic acetylcholine receptor subunit
Author: Leino, Sakari; Koski, Sini K.; Hänninen, Raisa; Tapanainen, Tuukka; Rannanpää, Saara; Salminen, Outi
Contributor: University of Helsinki, Regenerative pharmacology group
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Drug Research Program
Date: 2018-08
Language: eng
Number of pages: 10
Belongs to series: Neuropharmacology
ISSN: 0028-3908
URI: http://hdl.handle.net/10138/253492
Abstract: Preclinical studies suggest the involvement of various subtypes of nicotinic acetylcholine receptors in the pathophysiology of Parkinson's disease, a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNC). We studied for the first time the effects of alpha 5 nicotinic receptor subunit gene deletion on motor behavior and neurodegeneration in mouse models of Parkinson's disease and levodopa-induced dyskinesia. Unilateral dopaminergic lesions were induced in wild-type and alpha 5-KO mice by 6-hydroxydopamine injections into the striatum or the medial forebrain bundle. Subsequently, rotational behavior induced by dopaminergic drugs was measured. A subset of animals received chronic treatments with levodopa and nicotine to assess levodopa-induced dyskinesia and antidyskinetic effects by nicotine. SNC lesion extent was assessed with tyrosine hydroxylase immunohistochemistry and stereological cell counting. Effects of alpha 5 gene deletion on the dopaminergic system were investigated by measuring ex vivo striatal dopamine transporter function and protein expression, dopamine and metabolite tissue concentrations and dopamine receptor mRNA expression. Hemiparkinsonian alpha 5-KO mice exhibited attenuated rotational behavior after amphetamine injection and attenuated levodopa-induced dyskinesia. In the intrastriatal lesion model, dopaminergic cell loss in the medial cluster of the SNC was less severe in alpha 5-KO mice. Decreased striatal dopamine uptake in alpha 5-KO animals suggested reduced dopamine transporter function as a mechanism of attenuated neurotoxicity. Nicotine reduced dyskinesia severity in wild-type but not alpha 5-KO mice. The attenuated dopaminergic neurodegeneration and motor dysfunction observed in hemiparkinsonian alpha 5KO mice suggests potential for alpha 5 subunit-containing nicotinic receptors as a novel target in the treatment of Parkinson's disease. (C) 2018 The Authors. Published by Elsevier Ltd.
Subject: 317 Pharmacy
Parkinson's disease
Nicotinic receptors
Levodopa-induced dyskinesia
Chrna5 subunit
Substantia nigra
Dopamine
DOPA-INDUCED DYSKINESIAS
PARKINSONS-DISEASE
SUBSTANTIA-NIGRA
6-HYDROXYDOPAMINE
TRANSPORTER
STRIATUM
NEUROTOXICITY
RELEASE
PHOSPHORYLATION
MODULATION
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
1_s2.0_S0028390818303307_main.pdf 1.607Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record