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 α5 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 α5-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 α5 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 α5-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 α5-KO mice. Decreased striatal dopamine uptake in α5-KO animals suggested reduced dopamine transporter function as a mechanism of attenuated neurotoxicity. Nicotine reduced dyskinesia severity in wild-type but not α5-KO mice. The attenuated dopaminergic neurodegeneration and motor dysfunction observed in hemiparkinsonian α5-KO mice suggests potential for α5 subunit-containing nicotinic receptors as a novel target in the treatment of Parkinson's disease.
Highlights
Parkinson's disease is a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigraAbbreviations: 6-OHDA, 6-hydroxydopamine; Dopamine transporter (DAT), dopamine transporter; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; LID, levodopainduced dyskinesia; MFB, medial forebrain bundle; qPCR, quantitative polymerase chain reaction; RM-ANOVA, repeated measures analysis of variance; SNC, substantia nigra pars compacta; SNCD, dorsal tier of the SNC; SNCM, medial cluster of the SNC; TH, tyrosine hydroxylase.pars compacta (SNC), a deficit of dopamine in the dorsal striatum, and resulting motor deficits (Dauer and Przedborski, 2003)
The results suggest that the lack of a5* receptors resulted in attenuation of the hemiparkinsonian neurodegeneration and motor dysfunction induced by unilateral neurotoxic lesioning of the nigrostriatal dopaminergic pathway
The main finding of the study is that the death of dopaminergic neurons induced by intrastriatal injections of 6-OHDA was attenuated in a5-KO mice, within the medial cluster of the SNC (SNCM)
Summary
Parkinson's disease is a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra. Mice lacking the a5 subunit show impaired attention, increased anxiety, and decreased novelty-induced behavior as well as a decreased sensitivity to nicotine (Bailey et al, 2010; Besson et al, 2016; Jackson et al, 2010) Findings such as these suggest a key role for a5* receptors in a number of behavioral functions and illustrate their potential as a treatment target for various neurological and psychiatric disorders. Results obtained with selective ligands and subunit-null mice suggest that the neuroprotective effects are mediated by at least a4* and a7 nicotinic receptors (Bordia et al, 2015; Ryan et al, 2001), and that a4b2*, a6b2* and a7 nicotinic receptors all influence the expression of LID (Quik et al, 2013). We found that the lack of a5* nicotinic receptors resulted in attenuated dopaminergic pathophysiology, suggesting their potential as a novel target in the treatment of Parkinson's disease
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