Blockade of α6* nAChR Reduces L-Dopa-Induced Dyskinesias; Studies Using Parkinsonian α6* nAChR Gain-of-Function Mice

Abstract

L-Dopa-induced dyskinesias (LIDs) are a serious side effect of dopamine replacement therapy for Parkinson’s disease for which there are a few treatment options. Accumulating preclinical studies using nicotinic agonists and nicotinic receptor (nAChR) null mutant mice suggest a role for various nAChRs in LIDs, including the α6β2* nAChR population. Deletion of the α6 nAChR subunit reduced L-dopa-induced abnormal involuntary movements (AIMs) compared to wild type (WT) mice, while nicotine treatment reduced AIMs in WT but not in α6 nAChR knockout mice. To understand the mechanism through which α6β2* nAChRs regulate L-dopa-induced AIMs, we used gain-of-function α6* nAChR (α6L9’S) mice. This mutation results in enhanced sensitivity to nicotine/acetylcholine and prolonged receptor-mediated activity. Male WT and α6L9’S mice were lesioned by unilateral injection of 6-hydroxydopamine (3 µg/ml) into the medial forebrain bundle. Three to 4 wk later, they were rendered dyskinetic by administration of L-dopa (3 mg/kg) plus benserazide (15 mg/kg) for 3 wk. L-dopa-induced AIMs were expressed to a similar extent in the α6L9’S mice and WT mice. Three week later, when AIMs had stably developed, α6L9’S mice and WT mice were administered nicotine. WT mice were given nicotine in the drinking water in gradually increasing doses to a maximum of 300 µg/ml. This dose led to a 40% decline in L-dopa-induced AIMs. The reduction in AIMs in WT mice was maintained with doses of nicotine as low as 20 µg/ml. Because of their exquisite sensitivity to nicotine, α6L9’S mice received 10 µg/ml in the drinking water; higher nicotine doses resulted in mortality. In contrast to WT mice, nicotine treatment did not reduce L-dopa-induced AIMs in α6L9’S mice. To determine whether this may be due to enhanced activity of hypersensitive α6L9’S nAChRs, we tested the effect of the general nAChR blocker mecamylamine that has previously been shown to reduce L-dopa-induced AIMs. Two-day administration of mecamylamine (1 mg/kg ip 30 min before L-dopa) similarly reduced L-dopa-induced AIMs in α6L9’S mice and WT mice. The observation that a nAChR antagonist still reduced L-dopa-induced AIMs in α6L9’S mice suggests that nicotine decreases LIDs by a nAChR desensitization block. These results indicate that α6β2* nAChR antagonists may be useful for reducing L-dopa-induced dyskinesia.