title: Nicotinic receptor agonists decrease L-dopa-induced dyskinesias most effectively in partially lesioned parkinsonian rats.
abstract: L-dopa therapy for Parkinson's disease leads to dyskinesias or abnormal involuntary movement (AIMs) for which there are few treatment options. Our previous data showed that nicotine administration reduced L-dopa-induced AIMs in parkinsonian monkeys and rats. To further understand how nicotine mediates its antidyskinetic action, we investigated the effect of nicotinic receptor (nAChR) agonists in unilateral 6-OHDA-lesioned rats with varying striatal damage. We first tested the drugs in L-dopa-treated rats with a near-complete striatal dopamine lesion (>99%), the standard rodent dyskinesia model. Varenicline, an agonist that interacts with multiple nAChRs, did not significantly reduce L-dopa-induced AIMs, while 5-iodo-A-85380 (A-85380), which acts selectively at α4β2* and α6β2* subtypes, reduced AIMs by 20%. By contrast, both varenicline and A-85380 reduced L-dopa-induced AIMs by 40-50% in rats with a partial striatal dopamine lesion. Neither drug worsened the antiparkinsonian action of L-dopa. The results show that selective nicotinic agonists reduce dyskinesias, and that they are optimally effective in animals with partial striatal dopamine damage. These findings suggest that presynaptic dopamine terminal α4β2* and α6β2* nAChRs are critical for nicotine's antidyskinetic action. The current data have important implications for the use of nicotinic receptor-directed drugs for L-dopa-induced dyskinesias, a debilitating motor complication of dopamine replacement therapy for Parkinson's disease.
authors.affiliation: Center for Health Sciences, SRI International, 333 Ravenswood Ave, CA 94025, USA.
authors.forename: Luping Z
authors.initials: LZ
authors.lastname: Huang
authors.forename: Carla
authors.initials: C
authors.lastname: Campos
authors.forename: Jason
authors.initials: J
authors.lastname: Ly
authors.forename: F
authors.initials: F
authors.lastname: Ivy Carroll
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000037:antagonists & inhibitors; D001384:Azetidines / Q000494:pharmacology / Q000627:therapeutic use*; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000150:complications / Q000188:drug therapy*; D007980:Levodopa / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000150:complications / Q000188:drug therapy*; D011810:Quinoxalines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068580:Varenicline
chemical_list: C104288:A 85380; D000978:Antiparkinson Agents; D001384:Azetidines; D001552:Benzazepines; D050483:Dopamine Plasma Membrane Transport Proteins; D018722:Nicotinic Agonists; D011810:Quinoxalines; D007980:Levodopa; D016627:Oxidopamine; D000068580:Varenicline