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

T. Bordia, M. McGregor, J. M. McIntosh, R. M. Drenan, M. Quik*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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, 3μg/ml) into the medial forebrain bundle. Three to 4wk later, they were administered l-dopa (3mg/kg) plus benserazide (15mg/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 300μg/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 20μg/ml. However, the nAChR antagonist mecamylamine (1mg/kg ip 30min 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.

Original languageEnglish (US)
Pages (from-to)187-197
Number of pages11
JournalNeuroscience
Volume295
DOIs
StatePublished - Jun 4 2015

Keywords

  • 6-hydroxydopamine
  • Dyskinesia
  • L-dopa
  • Nicotine
  • Parkinson's disease

ASJC Scopus subject areas

  • Neuroscience(all)

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