title: Nicotine reduces L-DOPA-induced dyskinesias by acting at beta2* nicotinic receptors.
abstract: L-DOPA-induced dyskinesias or abnormal involuntary movements (AIMs) are a debilitating adverse complication associated with prolonged L-DOPA administration for Parkinson's disease. Few treatments are currently available for dyskinesias. Our recent data showed that nicotine reduced L-DOPA-induced AIMs in parkinsonian animal models. An important question is the nicotinic acetylcholine receptor (nAChR) subtypes through which nicotine exerts this beneficial effect, because such knowledge would allow for the development of drugs that target the relevant receptor population(s). To address this, we used β2 nAChR subunit knockout [β2(-/-)] mice because β2-containing nAChRs are key regulators of nigrostriatal dopaminergic function. All of the mice were lesioned by intracranial injection of 6-hydroxydopamine into the right medial forebrain bundle. Lesioning resulted in a similar degree of nigrostriatal damage and parkinsonism in β2(-/-) and wild-type mice. All of the mice then were injected with L-DOPA (3 mg/kg) plus benserazide (15 mg/kg) once daily for 4 weeks until AIMs were fully developed. L-DOPA-induced AIMs were approximately 40% less in the β2(-/-) mice compared with the wild-type mice. It is interesting to note that nicotine (300 μg/ml in drinking water) reduced L-DOPA-induced AIMs by 40% in wild-type mice but had no effect in β2(-/-) mice with partial nigrostriatal damage. The nicotine-mediated decline in AIMs was much less pronounced in wild-type mice with near-complete degeneration, suggesting that presynaptic nAChRs on dopaminergic terminals have a major influence. These data demonstrate an essential role for β2* nAChRs in the antidyskinetic effect of nicotine and suggest that drugs targeting these subtypes may be useful for the management of L-DOPA-induced dyskinesias in Parkinson's disease.
authors.affiliation: Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, California 94025, USA.
authors.forename: Luping Z
authors.initials: LZ
authors.lastname: Huang
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grady
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D001345:Autoradiography; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects; D003367:Cotinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D007839:Functional Laterality / Q000187:drug effects; D007980:Levodopa / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000378:metabolism / Q000494:pharmacology*; D016627:Oxidopamine; D011725:Pyridines / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013378:Substantia Nigra / Q000187:drug effects; D013565:Sympatholytics
chemical_list: D000978:Antiparkinson Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003367:Cotinine; D007980:Levodopa; D009538:Nicotine; D018722:Nicotinic Agonists; D016627:Oxidopamine; D011725:Pyridines; D011978:Receptors, Nicotinic; D013565:Sympatholytics; C082748:epibatidine