Nicotinic receptor-mediated reduction in L-DOPA-induced dyskinesias may occur via desensitization.
L-DOPA-induced dyskinesias in Parkinson's disease are a significant clinical problem for which few therapies are available. We recently showed that nicotine reduces L-DOPA-induced abnormal involuntary movements (AIMs) in parkinsonian animals, suggesting it may be useful for the treatment of L-DOPA-induced dyskinesias. The present experiments were performed to understand the mechanisms whereby nicotine reduces L-DOPA-induced AIMs. We used a well established model of dyskinesias, L-DOPA-treated unilateral 6-hydroxydopamine-lesioned rats. Dose-ranging studies showed that injection of 0.1 mg/kg nicotine once or twice daily for 4 or 10 days most effectively reduced AIMs, with no worsening of parkinsonism. Importantly, a single nicotine injection did not reduce AIMs, indicating that nicotine's effect is caused by long-term rather than short-term molecular changes. Administration of the metabolite cotinine did not reduce AIMs, suggesting a direct effect of nicotine. Experiments with the nicotinic receptor (nAChR) antagonist mecamylamine were done to determine whether nicotine acted via a receptor-mediated mechanism. Unexpectedly, several days of mecamylamine injection (1.0 mg/kg) alone significantly ameliorated dyskinesias to a comparable extent as nicotine. The decline in AIMs with combined nicotine and mecamylamine treatment was not additive, suggesting that nicotine exerts its effects via a nAChR interaction. This latter finding, combined with data showing that mecamylamine reduced AIMs to a similar extent as nicotine, and that nicotine or mecamylamine treatment both decreased alpha6beta2* and increased alpha4beta2* nAChR expression, suggests that the nicotine-mediated improvement in L-DOPA-induced AIMs may involve a desensitization block. These data have important implications for the treatment of L-DOPA-induced dyskinesias in Parkinson's disease.
Bordia
Tanuja
T
Center for Health Sciences, SRI International, Menlo Park, California 94025, USA.
Campos
Carla
C
McIntosh
J Michael
JM
Quik
Maryka
M
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002121:Calcium Channel Blockers; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003042:Cocaine / Q000031:analogs & derivatives; D020916:Conotoxins; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology* / Q000523:psychology; D007839:Functional Laterality / Q000187:drug effects; D007980:Levodopa; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011725:Pyridines; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*; D013239:Stereotyped Behavior / Q000187:drug effects
D000978:Antiparkinson Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002121:Calcium Channel Blockers; D000697:Central Nervous System Stimulants; D020916:Conotoxins; D050483:Dopamine Plasma Membrane Transport Proteins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; C559463:alpha6beta2 nicotinic acetylcholine receptor; C403531:nicotinic receptor alpha4beta2; C079213:RTI 121; D007980:Levodopa; D008464:Mecamylamine; D009538:Nicotine; D000661:Amphetamine; D003042:Cocaine; C082748:epibatidine