α4β2 nicotinic receptors play a role in the nAChR-mediated decline in L-dopa-induced dyskinesias in parkinsonian rats

NEUROPHARMACOLOGY

卷:71

Article

Quik, Maryka¹  Campos, Carla¹  Bordia, Tanuja¹  Strachan, Jon-Paul²  Zhang, Jenny²  McIntosh, J. Michael³  Letchworth, Sharon²  Jordan, Kristen² 

[1] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA

[2] Targacept Inc, Winston Salem, NC USA

[3] Univ Utah, Dept Biol & Psychiat, Salt Lake City, UT USA

关键词: Dyskinesia;    L-dopa;    Nicotine;    Nicotinic;    Parkinson's disease;    Sazetidine;   

DOI  :  10.1016/j.neuropharm.2013.03.038

来源: Elsevier

【 摘 要 】

L-dopa-induced dyskinesias are a serious long-term side effect of dopamine replacement therapy for Parkinson's disease for which there are few treatment options. Our previous studies showed that nicotine decreased L-dopa-induced abnormal involuntary movements (AIMs). Subsequent work with knockout mice demonstrated that alpha 6 beta 2* nicotinic receptors (nAChRs) play a key role. The present experiments were done to determine if alpha 4 beta 2* nAChRs are also involved in L-dopa-induced dyskinesias. To approach this, we took advantage of the finding that alpha 6 beta 2* nAChRs are predominantly present on striatal dopaminergic nerve terminals, while a significant population of alpha 4 beta 2* nAChRs are located on other neurons. Thus, a severe dopaminergic lesion would cause a major loss in alpha 6 beta 2*, but not alpha 4 beta 2* nAChRs. Experiments were therefore done in which rats were unilaterally lesioned with 6-hydroxydopamine, at a dose that led to severe nigrostriatal damage. The dopamine transporter, a dopamine nerve terminal marker, was decreased by >99%. This lesion also decreased striatal alpha 6 beta 2* nAChRs by 97%, while alpha 4 beta 2* nAChRs were reduced by only 12% compared to control. A series of beta 2* nAChR compounds, including TC-2696, TI-10165, TC-8831, TC-10600 and sazetidine reduced L-dopa-induced AIMs in these rats by 23-32%. TC-2696, TI-10165, TC-8831 were also tested for parkinsonism, with no effect on this behavior. Tolerance did not develop with up to 3 months of treatment. Since alpha 4 alpha 5 beta 2 nAChRs are also predominantly on striatal dopamine terminals, these data suggest that drugs targeting alpha 4 beta 2 nAChRs may reduce L-dopa-induced dyskinesias in late stage Parkinson's disease. (C) 2013 Elsevier Ltd. All rights reserved.

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