The α7 nicotinic receptor agonist ABT-107 decreases L-Dopa-induced dyskinesias in parkinsonian monkeys.

Abstract

Previous studies in Parkinsonian rats and monkeys have shown that β2-selective nicotinic acetylcholine receptor (nAChR) agonists reduce l-Dopa-induced dyskinesias (LIDs), a serious complication of l-Dopa therapy for Parkinson's disease. Since rodent studies also suggested an involvement of α7 nAChRs in LIDs, we tested the effect of the potent, selective α7 agonist ABT-107 [5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole]. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned monkeys were gavaged with l-Dopa/carbidopa (10 and 2.5 mg/kg, respectively) twice daily, which resulted in stable LIDs. A dose-response study (0.03-1.0 mg/kg) showed that oral ABT-107 decreased LIDs by 40-60%. LIDs returned to control levels only after a 6-week ABT-107 washout, suggesting that long-term molecular changes were involved. Subsequent readministration of ABT-107 decreased LIDs by 50-60%, indicating that tolerance did not develop. ABT-107 had no effect on Parkinsonism or cognitive performance. We next tested ABT-107 together with the β2 agonist ABT-894 [(3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane], previously shown to reduce LIDs in Parkinsonian monkeys. In one study, the monkeys were first given oral ABT-894 (0.01 mg/kg), which maximally decreased LIDs by 50-60%; they were then also treated with 0.1 mg/kg ABT-107, a dose that maximally reduced LIDs. The effect of combined treatment on LIDs was similar to that with either drug alone. Comparable results were observed in a group of monkeys first treated with ABT-107 and then also given ABT-894. Thus, α7 and β2 nAChR-selective drugs may function via a final common mechanism to reduce LIDs. The present results suggest that drugs targeting either α7 or β2 nAChRs may be useful as antidyskinetic agents in Parkinson's disease.