SK channel blockade reverses cognitive and motor deficits induced by nigrostriatal dopamine lesions in rats
SK channel blockade reverses cognitive and motor deficits induced by nigrostriatal dopamine lesions in rats
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DOI：
10.1017/s1461145714000236
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发表时间：
2014-08-01
影响因子：
4.8
通讯作者：
Mourre, Christiane
中科院分区：
文献类型：
--
作者：
Chen, Lin;Deltheil, Thierry;Mourre, Christiane
帕金森病传统上被认为是一种运动障碍引起的多巴胺（DA）神经元的损失。然而，情绪和认知综合征可以先于运动缺陷的发作，并提供治疗干预的机会。钾离子通道最近成为帕金森病治疗的潜在新靶点。已知apamin选择性阻断小电导钙激活K+通道（SK通道）可增加中脑DA神经元的爆发放电，从而增加DA释放。因此，我们研究了全身给药的apamin对运动，认知缺陷和焦虑的影响后，双边黑质纹状体6-羟基多巴胺（6-OHDA）的病变大鼠。Apamin给药（0.1或0.3 mg/kg i.p.）抵消了在蔗糖消耗和高架十字迷宫中评估的抑郁、焦虑样行为、由部分6-OHDA损伤产生的社会识别和空间记忆缺陷。Apamin还减少了单侧广泛6-OHDA模型中绕圈行为和姿势调整的不对称运动缺陷。部分6-OHDA病变（56%纹状体DA耗竭）产生20%的减少与酪氨酸羟化酶阳性细胞的损失相关的黑质丘脑部碘化apamin结合位点，而不修改apamin结合在大脑区域接受DA能神经支配。纹状体细胞外水平的DA，6-OHDA病变后检测不到，提高了蜂毒肽治疗在体内微透析测量。这些结果表明，阻断SK通道可以恢复纹状体中最小的DA活性，以减轻由部分纹状体DA损伤引起的非运动症状。
Parkinson's disease has traditionally been viewed as a motor disorder caused by the loss of dopamine (DA) neurons. However, emotional and cognitive syndromes can precede the onset of the motor deficits and provide an opportunity for therapeutic intervention. Potassium channels have recently emerged as potential new targets in the treatment of Parkinson's disease. The selective blockade of small conductance calcium-activated K+ channels (SK channels) by apamin is known to increase burst firing in midbrain DA neurons and therefore DA release. We thus investigated the effects of systemic administration of apamin on the motor, cognitive deficits and anxiety present after bilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesions in rats. Apamin administration (0.1 or 0.3 mg/kg i.p.) counteracted the depression, anxiety-like behaviors evaluated on sucrose consumption and in the elevated plus maze, social recognition and spatial memory deficits produced by partial 6-OHDA lesions. Apamin also reduced asymmetric motor deficits on circling behavior and postural adjustments in the unilateral extensive 6-OHDA model. The partial 6-OHDA lesions (56% striatal DA depletion) produced 20% decrease of iodinated apamin binding sites in the substantia nigra pars compacta in correlation with the loss of tyrosine hydroxylase positive cells, without modifying apamin binding in brain regions receiving DAergic innervation. Striatal extracellular levels of DA, not detectable after 6-OHDA lesions, were enhanced by apamin treatment as measured by in vivo microdialysis. These results indicate that blocking SK channels may reinstate minimal DA activity in the striatum to alleviate the non-motor symptoms induced by partial striatal DA lesions.