title: Evidence for a role for α6(∗) nAChRs in l-dopa-induced dyskinesias using Parkinsonian α6(∗) nAChR gain-of-function mice.
abstract: l-Dopa-induced dyskinesias (LIDs) are a serious side effect of dopamine replacement therapy for Parkinson's disease. The mechanisms that underlie LIDs are currently unclear. However, preclinical studies indicate that nicotinic acetylcholine receptors (nAChRs) play a role, suggesting that drugs targeting these receptors may be of therapeutic benefit. To further understand the involvement of α6β2(∗) nAChRs in LIDs, we used gain-of-function α6(∗) nAChR (α6L9S) mice that exhibit a 20-fold enhanced sensitivity to nAChR agonists. Wildtype (WT) and α6L9S mice were lesioned by unilateral injection of 6-hydroxydopamine (6-OHDA, 3μg/ml) into the medial forebrain bundle. Three to 4wk later, they were administered l-dopa (3mg/kg) plus benserazide (15mg/kg) until stably dyskinetic. l-dopa-induced abnormal involuntary movements (AIMs) were similar in α6L9S and WT mice. WT mice were then given nicotine in the drinking water in gradually increasing doses to a final 300μg/ml, which resulted in a 40% decline AIMs. By contrast, there was no decrease in AIMs in α6L9S mice at a maximally tolerated nicotine dose of 20μg/ml. However, the nAChR antagonist mecamylamine (1mg/kg ip 30min before l-dopa) reduced l-dopa-induced AIMs in both α6L9S and WT mice. Thus, both a nAChR agonist and antagonist decreased AIMs in WT mice, but only the antagonist was effective in α6L9S mice. Since nicotine appears to reduce LIDs via desensitization, hypersensitive α6β2(∗) nAChRs may desensitize less readily. The present data show that α6β2(∗) nAChRs are key regulators of LIDs, and may be useful therapeutic targets for their management in Parkinson's disease.
authors: Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA.
authors: T
authors: T
authors: Bordia
authors: Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA.
authors: M
authors: M
authors: McGregor
authors: George E. Wahlen Veterans Affairs Medical Center, Department of Psychiatry, University of Utah, Salt Lake City, UT 84148, USA; Department of Biology, University of Utah, Salt Lake City, UT 84148, USA.
authors: J M
authors: JM
authors: McIntosh
authors: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
authors: R M
authors: RM
authors: Drenan
authors: Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA. Electronic address: maryka.quik@sri.com.
authors: M
authors: M
authors: Quik
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001545:Benserazide / Q000627:therapeutic use; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009538:Nicotine / Q000627:therapeutic use; D018722:Nicotinic Agonists / Q000627:therapeutic use; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy; D011485:Protein Binding / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*
chemical_list: D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C559463:alpha6beta2 nicotinic acetylcholine receptor; C079213:RTI 121; D007980:Levodopa; D009538:Nicotine; D001545:Benserazide; D016627:Oxidopamine; D003042:Cocaine
keywords: 6-hydroxydopamine; Parkinson’s disease; dyskinesia; l-dopa; nicotine