Effects of striatal injections of GABAA receptor agonists and antagonists in a genetic animal model of paroxysmal dystonia
Effects of striatal injections of GABAA receptor agonists and antagonists in a genetic animal model of paroxysmal dystonia
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DOI：
10.1016/s0014-2999(02)01546-7
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发表时间：
2002-05-17
影响因子：
5
通讯作者：
Richter, A
中科院分区：
文献类型：
--
作者：
Hamann, M;Richter, A
特发性肌张力障碍的潜在机制尚不清楚。Dt(Sz)突变仓鼠是一种阵发性肌张力障碍的模型，其肌张力障碍的表型是基于纹状体中GABA能中间神经元的缺失和GABA(A)-苯二氮卓类受体复合体的变化。为了证实和扩展先前的观察，在纹状体微量注射后，与DT(Sz)突变体的全身治疗相比较，测定了与GABA(A)受体不同位置结合的化合物对肌张力障碍严重程度的影响。GABA(A)受体激动剂(麝香酚)和苯二氮卓类药物(氟拉西潘)可减轻纹状体和全身注射后肌张力障碍的严重程度。巴比妥酸苯巴比妥在纹状体和腹膜腔给药后的抗张力障碍作用均不明显。纹状体内注射GABA延迟了肌张力障碍发作的发生。用GABA(A)受体拮抗剂荷包牡丹碱和降低GABA能功能的戊四唑进行纹状体和全身治疗，在亚惊厥剂量下会加速肌张力障碍的发生。苯二氮卓类受体拮抗剂氟马西尼加重全身和纹状体注射后的肌张力障碍。总之，目前的数据证实了纹状体GABA能去抑制在dt(Sz)突变型阵发性肌张力障碍的发病机制中的相关性。(C)2002年，爱思唯尔科学公司出版。
The underlying mechanisms of idiopathic dystonias are poorly understood. The dystonic phenotype in the dt(sz) mutant hamster, a model of paroxysmal dystonia, has been suggested to be based on a deficit of gamma-aminobutyric acid (GABA)ergic interneurons and changes of the GABA(A)-benzodiazepine receptor complex in the striatum. In order to confirm and extend previous observations, the effects of compounds which bind to different sites of the GABA(A) receptor on the severity of dystonia were determined after striatal microinjections in comparison to systemic treatments in dt(sz) mutants. The GABA(A) receptor agonist (muscimol) and the benzodiazepine (flurazepam) reduced the severity of dystonia after striatal and systemic injections. The antidystonic effects of the barbiturate phenobarbital were less marked both after striatal and intraperitoneal administration of drugs. Intrastriatal injections of GABA delayed the onset of dystonic attacks. Striatal and systemic treatments with the GABA(A) receptor antagonist, bicuculline, and with pentylenetetrazole, which reduces GABAergic function, accelerated the onset of dystonia at subconvulsant doses. The benzodiazepine receptor antagonists flumazenil aggravated dystonia after systemic and intrastriatal injections. In all, the present data substantiate the relevance of striatal GABAergic disinhibition in the pathogenesis of paroxysmal dystonia in dt(sz) mutants. (C) 2002 Published by Elsevier Science B.V.