PT  - JOURNAL ARTICLE
AU  - Zhang, Danhui
AU  - Mallela, Archana
AU  - Sohn, David
AU  - Carroll, F. Ivy
AU  - Bencherif, Merouane
AU  - Letchworth, Sharon
AU  - Quik, Maryka
TI  - Nicotinic Receptor Agonists Reduce <span class="sc">l</span>-DOPA–Induced Dyskinesias in a Monkey Model of Parkinson's Disease
AID  - 10.1124/jpet.113.207639
DP  - 2013 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 225--234
VI  - 347
IP  - 1
4099  - http://jpet.aspetjournals.org/content/347/1/225.short
4100  - http://jpet.aspetjournals.org/content/347/1/225.full
SO  - J Pharmacol Exp Ther2013 Oct 01; 347
AB  - Abnormal involuntary movements or dyskinesias are a serious complication of long-term l-DOPA treatment of Parkinson’s disease, for which there are few treatment options. Accumulating preclinical data show that nicotine decreases l-DOPA–induced dyskinesias (LIDs), suggesting that it may be a useful antidyskinetic therapy for Parkinson’s disease. Here, we investigated whether nicotinic acetylcholine receptor (nAChR) agonists reduced LIDs in nonhuman primates. We first tested the nonselective nAChR agonist 1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (varenicline), which offers the advantage that it is approved by the U.S. Food and Drug Administration for use in humans. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–lesioned monkeys (n = 23) were first administered l-DOPA/carbidopa (10/2.5 mg/kg) twice daily 5 days/week until stably dyskinetic. Oral varenicline (0.03–0.10 mg/kg) decreased LIDs ∼50% compared with vehicle-treated monkeys, whereas nicotine treatment (300 µg/ml in drinking water) reduced LIDs by 70% in a parallel group of animals. We next tested the selective α4β2*/α6β2* nAChR agonist TC-8831 [3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane] on LIDs in the same set of monkeys after a 10-week washout. We also tested TC-8831 in another set of MPTP-lesioned monkeys (n = 16) that were nAChR drug–naïve. Oral TC-8831 (0.03–0.3 mg/kg) reduced LIDs in both sets by 30–50%. After a washout period, repeat TC-8831 dosing led to a greater decline in LIDs (60%) in both sets of monkeys that was similar to the effect of nicotine. Tolerance to any nAChR drug did not develop over the course of the study (3–4 months). NAChR drug treatment did not worsen parkinsonism or cognitive ability. These data suggest that nAChR agonists may be useful for the management of dyskinesias in l-DOPA–treated Parkinson’s disease patients.