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

Neuroscience. 2015 Jun 4:295:187-97. doi: 10.1016/j.neuroscience.2015.03.040. Epub 2015 Mar 24.

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.

Keywords: 6-hydroxydopamine; Parkinson’s disease; dyskinesia; l-dopa; nicotine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic Agents / toxicity
  • Analysis of Variance
  • Animals
  • Antiparkinson Agents / adverse effects*
  • Benserazide / therapeutic use
  • Cocaine / analogs & derivatives
  • Cocaine / pharmacokinetics
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Dyskinesia, Drug-Induced / drug therapy
  • Dyskinesia, Drug-Induced / etiology*
  • Dyskinesia, Drug-Induced / metabolism*
  • Levodopa / adverse effects*
  • Male
  • Mice
  • Mice, Transgenic
  • Nicotine / therapeutic use
  • Nicotinic Agonists / therapeutic use
  • Oxidopamine / toxicity
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / drug therapy
  • Protein Binding / drug effects
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism*

Substances

  • Adrenergic Agents
  • Antiparkinson Agents
  • Nicotinic Agonists
  • Receptors, Nicotinic
  • alpha6beta2 nicotinic acetylcholine receptor
  • RTI 121
  • Levodopa
  • Nicotine
  • Benserazide
  • Oxidopamine
  • Cocaine