title: Multiple CNS nicotinic receptors mediate L-dopa-induced dyskinesias: studies with parkinsonian nicotinic receptor knockout mice.
abstract: Accumulating evidence supports the idea that drugs acting at nicotinic acetylcholine receptors (nAChRs) may be beneficial for Parkinson's disease, a neurodegenerative movement disorder characterized by a loss of nigrostriatal dopaminergic neurons. Nicotine administration to parkinsonian animals protects against nigrostriatal damage. In addition, nicotine and nAChR drugs improve L-dopa-induced dyskinesias, a debilitating side effect of L-dopa therapy which remains the gold-standard treatment for Parkinson's disease. Nicotine exerts its antidyskinetic effect by interacting with multiple nAChRs. One approach to identify the subtypes specifically involved in L-dopa-induced dyskinesias is through the use of nAChR subunit null mutant mice. Previous work with β2 and α6 nAChR knockout mice has shown that α6β2* nAChRs were necessary for the development/maintenance of L-dopa-induced abnormal involuntary movements (AIMs). The present results in parkinsonian α4 nAChR knockout mice indicate that α4β2* nAChRs also play an essential role since nicotine did not reduce L-dopa-induced AIMs in such mice. Combined analyses of the data from α4 and α6 knockout mice suggest that the α6α4β2β3 subtype may be critical. In contrast to the studies with α4 and α6 knockout mice, nicotine treatment did reduce L-dopa-induced AIMs in parkinsonian α7 nAChR knockout mice. However, α7 nAChR subunit deletion alone increased baseline AIMs, suggesting that α7 receptors exert an inhibitory influence on L-dopa-induced AIMs. In conclusion, α6β2*, α4β2* and α7 nAChRs all modulate L-dopa-induced AIMs, although their mode of regulation varies. Thus drugs targeting one or multiple nAChRs may be optimal for reducing L-dopa-induced dyskinesias in Parkinson's disease.
authors.affiliation: Center for Health Sciences, SRI International, 333 Ravenswood Avenue, CA 94025, USA. Electronic address: maryka.quik@sri.com.
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
authors.forename: Carla
authors.initials: C
authors.lastname: Campos
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grady
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000502:physiology*; D003367:Cotinine / Q000097:blood; D004298:Dopamine / Q000633:toxicity*; D020820:Dyskinesias / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009538:Nicotine / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D012439:Saccharin; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D003367:Cotinine; D004298:Dopamine; D009538:Nicotine; D011978:Receptors, Nicotinic; D012439:Saccharin; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: *; Dyskinesias; Nicotine; Nicotinic receptors; Parkinson's disease; Striatum; nAChR; nicotinic acetylcholine receptor; the possible presence of other subunits in the receptor complex; α-CtxMII; α-conotoxinMII