Inhibition of levodopa-induced abnormal involuntary movements (AIMs) using a selective α7 nicotinic positive allosteric modulator

Chronic administration of nicotine and nicotinic ligands have been shown to reduce levodopa-induced dyskinesia (LID) in rodents and primates. Due to its unique extra-striatal localisation and biochemical signalling properties, the α7 subtype of nicotinic acetylcholine receptors (nAChRs) may represent an important and unique target for drug development for the treatment of dyskinesia, particularly since positive allosteric modulator (PAM) at the α7 nAChRs subtype may provide an opportunity to reduce dyskinesia without side effects. In this study, we report on the anti-dyskinetic actions of a selective α7 PAM, PNU-120596 and compared its action to nicotine and other α7 nAChRs ligands. Unilaterally 6-OHDA lesioned female rats were primed with levodopa to display abnormal involuntary movements (AIMs) to model levodopa-induced dyskinesia. The effects of the α7 PAM, PNU-120596, an α7 agonist, PHA-543613 or the α7 antagonist, methyllycaconitine (MLA), as well as nicotine, a non-selective nAChR agonist were all examined on AIMs. Low doses of PNU-120596 and nicotine dose-dependently reduced AIMs, but combination of the PAM with nicotine produced only an additive effect which surprisingly, could not be demonstrated with the α7 agonist PHA-543613, while MLA dose-dependently reduced AIMS. The effects of PNU-120596 suggests that α7 PAMs may enhance the effect of basal acetylcholine on α7 receptors in the striatum and may provide a new avenue for the treatment of levodopa-induced dyskinesia. Reduction of AIMs by MLA suggests that the mechanism of AIMs reduction may involve the rapid desensitization of the α7 nAChRs subtype.