Evidence for a role for α6∗ nAChRs in l-dopa-induced dyskinesias using parkinsonian α6∗ nAChR gain-of-function mice

•Chronic nicotine treatment reduces AIMs in WT but not α6L9'S mice.•The nAChR antagonist mecamylamine reduces AIMs in both WT and α6L9'S mice.•Nicotine may decrease AIMs via desensitization blockade of α6 nAChRs.•α6∗ nAChR antagonists may be useful for reducing LIDs.

l-Dopa-induced dyskinesias (LIDs) are a serious side effect of dopamine replacement therapy for Parkinson's disease. The mechanisms that underlie LIDs are currently unclear. However, preclinical studies indicate that nicotinic acetylcholine receptors (nAChRs) play a role, suggesting that drugs targeting these receptors may be of therapeutic benefit. To further understand the involvement of α6β2∗ nAChRs in LIDs, we used gain-of-function α6∗ nAChR (α6L9S) mice that exhibit a 20-fold enhanced sensitivity to nAChR agonists. Wildtype (WT) and α6L9S mice were lesioned by unilateral injection of 6-hydroxydopamine (6-OHDA, 3 μg/ml) into the medial forebrain bundle. Three to 4 wk later, they were administered l-dopa (3 mg/kg) plus benserazide (15 mg/kg) until stably dyskinetic. l-dopa-induced abnormal involuntary movements (AIMs) were similar in α6L9S and WT mice. WT mice were then given nicotine in the drinking water in gradually increasing doses to a final 300 μg/ml, which resulted in a 40% decline AIMs. By contrast, there was no decrease in AIMs in α6L9S mice at a maximally tolerated nicotine dose of 20 μg/ml. However, the nAChR antagonist mecamylamine (1 mg/kg ip 30 min before l-dopa) reduced l-dopa-induced AIMs in both α6L9S and WT mice. Thus, both a nAChR agonist and antagonist decreased AIMs in WT mice, but only the antagonist was effective in α6L9S mice. Since nicotine appears to reduce LIDs via desensitization, hypersensitive α6β2∗ nAChRs may desensitize less readily. The present data show that α6β2∗ nAChRs are key regulators of LIDs, and may be useful therapeutic targets for their management in Parkinson's disease.