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.