The anti-dyskinetic effect of dopamine receptor blockade is enhanced in parkinsonian rats following dopamine neuron transplantation

NEUROBIOLOGY OF DISEASE

卷:62

Article

Shin, Eunju¹  Lisci, Carlo²  Tronci, Elisabetta²  Fidalgo, Camino²  Stancampiano, Roberto²  Bjorklund, Anders¹  Carta, Manolo² 

[1] Lund Univ, Div Neurobiol, Wallenberg Neurosci Ctr, S-22184 Lund, Sweden

[2] Univ Cagliari, Dept Biomed Sci, I-09042 Monserrato, Italy

关键词: Graft-induced dyskinesia;    L-DOPA-induced dyskinesia;    Parkinson's disease;    Dopamine D-1 receptor;    Dopamine D-2 receptor;    Eticlopride;    SCH23390;    Buspirone;    Cell transplantation;   

DOI  :  10.1016/j.nbd.2013.09.021

来源: Elsevier

【 摘 要 】

Graft-induced dysldnesia (GID) is a serious complication induced by dopamine (DA) cell transplantation in parkinsonian patients. We have recently shown that DA D-2 receptor blockade produces striking blockade of dyskinesia induced by amphetamine in grafted 6-0HDA-lesioned rats, a model of GID. This study was designed to investigate whether blockade of DA D-1 receptors could produce similar outcome, and to see whether the effect of these treatments in grafted rats was specific for dyskinesia induced by amphetamine, or could also influence L-DOPA-induced dyskinesia (UD). L-DOPA-primed rats received transplants of fetal DA neurons into the DA-denervated striatum. Beginning at 20 weeks after transplantation rats were subjected to pharmacological treatments with either L-DOPA (6 mg/kg) or amphetamine (1.5 mg/kg) alone, or in combination with the D1 receptor antagonist SCH23390, the D-2 receptor antagonist etidopride, and the 5-HT-IA agonist/D-2 receptor antagonist buspirone. Grafted rats developed severe GID, while LID was reduced. Both etidopride and SCH23390 produced near-complete suppression of GID already at very low doses (0.015 and 0.1 mg/kg, respectively). Buspirone induced similar suppression at a dose as low as 0.3 mg/kg, which is far lower than the dose known to affect LID in non-grafted dyskinetic rats. In agreement with our previous results, the effect of buspirone was independent from 5-HTiA receptor activation, as it was not counteracted by the selective 5HT1A antagonist WAY100635, but likely due to D-2 receptor blockade. Most interestingly, the same doses of etidopride, SCH23390 and buspirone were found to suppress LID in grafted but not in control dyskinetic rats. Taken together, these data demonstrate that the DA cell grafts strikingly exacerbate the effect of DA DI and D-2 receptor blockade against both GID and LID, and suggest that the anti-GID effect of buspirone seen in patients may also be due to blockade of DA D-2 receptors. (C) 2013 Elsevier Inc. All rights reserved.

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