| First Author | Bordia T | Year | 2015 |
| Journal | Neuroscience | Volume | 295 |
| Pages | 187-97 | PubMed ID | 25813704 |
| Mgi Jnum | J:222645 | Mgi Id | MGI:5645171 |
| Doi | 10.1016/j.neuroscience.2015.03.040 | Citation | Bordia T, et al. (2015) Evidence for a role for alpha6( *) nAChRs in l-dopa-induced dyskinesias using Parkinsonian alpha6( *) nAChR gain-of-function mice. Neuroscience 295:187-97 |
| abstractText | 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 alpha6beta2( *) nAChRs in LIDs, we used gain-of-function alpha6( *) nAChR (alpha6L9S) mice that exhibit a 20-fold enhanced sensitivity to nAChR agonists. Wildtype (WT) and alpha6L9S mice were lesioned by unilateral injection of 6-hydroxydopamine (6-OHDA, 3mug/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 alpha6L9S and WT mice. WT mice were then given nicotine in the drinking water in gradually increasing doses to a final 300mug/ml, which resulted in a 40% decline AIMs. By contrast, there was no decrease in AIMs in alpha6L9S mice at a maximally tolerated nicotine dose of 20mug/ml. However, the nAChR antagonist mecamylamine (1mg/kg ip 30min before l-dopa) reduced l-dopa-induced AIMs in both alpha6L9S and WT mice. Thus, both a nAChR agonist and antagonist decreased AIMs in WT mice, but only the antagonist was effective in alpha6L9S mice. Since nicotine appears to reduce LIDs via desensitization, hypersensitive alpha6beta2( *) nAChRs may desensitize less readily. The present data show that alpha6beta2( *) nAChRs are key regulators of LIDs, and may be useful therapeutic targets for their management in Parkinson's disease. |
