title: Role for α6 nicotinic receptors in l-dopa-induced dyskinesias in parkinsonian mice.
abstract: L-Dopa-induced dyskinesias are a serious side effect that develops in most Parkinson's disease patients on dopamine replacement therapy. Few treatment options are available to manage dyskinesias; however,recent studies show that nicotine reduces these abnormal involuntary movements (AIMs) in parkinsonian animals by acting at nicotinic acetylcholine receptors (nAChRs). Identification of the nAChR subtypes that mediate this reduction in AIMs is important as it will help in the development of nAChR subtype selective drugs for their treatment. Here we investigate the role of α6β2* nAChRs, a subtype selectively present in the nigrostriatal pathway, using a6 nAChR subunit null mutant (α6⁻/⁻) mice.Wildtype and α6⁻/⁻ mice were lesioned by unilateral injection of 6-hydroxydopamine (3 mg/ml) into the medial forebrain bundle. They were then given L-dopa (3 mg/kg) plus benserazide (15 mg/kg) 2e3 wk later. L-dopa-induced AIMs developed to a similar extent in α6⁻/⁻ and wildtype mice.However, AIMs in α6⁻/⁻ mice declined to ~50% of that in wildtype mice with continued L-dopa treatment. Nicotine treatment also decreased AIMs by ~50% in wildtype mice, although not in α6⁻/⁻ mice. There were no effects on parkinsonism under any experimental condition. To conclude, the similar declines in L-dopa-induced AIMs in nicotine-treated wildtype mice and in α6⁻/⁻ mice treated with and without nicotine indicate an essential role for α6β2* nAChRs in the maintenance of L-dopa-induced AIMs.These findings suggest that α6β2* nAChR drugs have potential for reducing L-dopa-induced dyskinesias in Parkinson's disease.
authors.affiliation: Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USA. maryka.quik@sri.com
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
authors.forename: Keon Min
authors.initials: KM
authors.lastname: Park
authors.forename: Maya
authors.initials: M
authors.lastname: Hrachova
authors.forename: Archana
authors.initials: A
authors.lastname: Mallela
authors.forename: Luping Z
authors.initials: LZ
authors.lastname: Huang
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grady
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D001345:Autoradiography; D001545:Benserazide / Q000494:pharmacology; D003367:Cotinine / Q000097:blood; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D006892:Hydroxydopamines; D007980:Levodopa / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000503:physiopathology*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology*
chemical_list: D000978:Antiparkinson Agents; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D006892:Hydroxydopamines; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C559463:alpha6beta2 nicotinic acetylcholine receptor; C104518:nicotinic receptor alpha6; D007980:Levodopa; D009538:Nicotine; D001545:Benserazide; D003367:Cotinine; D004298:Dopamine