Aquaporin‐4 Knockout Abolishes Apomorphine‐Induced Tardive Dyskinesia Following Chronic Treatment with Neuroleptics
Aquaporin‐4 Knockout Abolishes Apomorphine‐Induced Tardive Dyskinesia Following Chronic Treatment with Neuroleptics
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DOI：
10.1111/cns.12020
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发表时间：
2012-12
影响因子：
5.5
通讯作者：
Cun-Jin Su;Xiao-qing Xu;Yi Fan;Ren-Hong Du;G. Hu
中科院分区：
文献类型：
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作者：
Cun-Jin Su;Xiao-qing Xu;Yi Fan;Ren-Hong Du;G. Hu
迟发性运动障碍（TD）是一种长期服用典型的精神抑制剂（如氟哌啶醇）的副作用，其特征是面部、口腔、舌头以及身体其他部位的过度和不自主运动[1]。相反，非典型抗精神病药物如氯氮平显示TD风险降低[2]。然而，典型和非典型抗精神病药物对TD的不同作用的神经化学机制仍不清楚[3]。多巴胺能功能的减弱，特别是多巴胺（DA）受体的超敏性，已被证明参与TD的病理生理学[4]。多巴胺超敏反应的行为证据在许多不同的动物模型中得到证实。D2多巴胺受体的上调被认为是导致行为敏感性发展的主要机制[4]。阿扑吗啡（APO）是一种非选择性D1/D2激动剂，在长期使用抗精神病药物治疗后可诱导刻板行为和空咀嚼运动（VCM），并常规用作TD的实验模型[5]。水通道蛋白-4（AQP 4）是脑内主要的水通道，在血管周围星形胶质细胞终足中高度表达，在中枢神经系统中起关键作用[6]。AQP 4基因敲除可增加不同脑区DA的合成和周转。目前，多条证据表明AQP 4参与异常多巴胺能神经传递诱导的疾病，如帕金森病[7]、成瘾[8]和情绪障碍。然而，AQP 4在TD中的意义仍不清楚。本研究以AQP 4基因敲除小鼠（AQP 4/）为研究对象，探讨AQP 4在TD发病中的作用。给15周龄雄性AQP 4和AQP 4/小鼠注射氟哌啶醇（2 mg/kg i. p.），氯氮平（10 mg/kg i. p.），或生理盐水每天一次，持续21天。末次注射后，使用ZIL-2活动仪（中国医学科学院）监测运动活动。将小鼠放入活动监测室（20厘米9 - 20厘米）10分钟，然后以10分钟的间隔测量活动。随后，小鼠接受APO注射（1 mg/kg，s.c.）。注射后，记录接下来10分钟间隔的活动次数。如图1所示，氟哌啶醇和氯氮平对AQP 4和AQP 4/小鼠的运动活动均显示出显著的抑制作用。在两种基因型小鼠中，典型抗精神病药物氟哌啶醇在抑制自发活动方面比非典型抗精神病药物氯氮平更有效（图1A）。AQP 4基因敲除不影响这些行为差异的自发活动。AQP 4小鼠在APO刺激后表现出明显的过度运动。值得注意的是，AQP 4敲除消除了慢性精神抑制剂和盐水治疗后APO诱导的过度运动（图1B）。结果表明，AQP 4基因敲除可直接阻断APO的精神兴奋作用。在啮齿类动物中，长期给予精神抑制剂诱导的过度咀嚼运动是最广泛使用的TD现象学动物模型[5]。VCM被称为在垂直平面上的单口开口，不指向物理材料。在末次注射后3天计数VCM数量。将小鼠单独放入无食物的透明观察笼（16 cm 9 30 cm 9 19 cm）中，持续1小时的适应期。注射APO（1 mg/kg，s.c.）后5 min，以5 min间隔测量VCM。结果发现，氟哌啶醇预处理组在APO刺激下，AQP 4小鼠血管平滑肌细胞数量明显增加，而氯氮平预处理组无此现象。然而，在AQP 4/小鼠中，经氟哌啶醇、氯氮平或
Tardive dyskinesia (TD) is a side effect of long-term administration of typical neuroleptics such as haloperidol, and is characterized by excessive and involuntary movements of the face, mouth, tongue as well as other parts of the body [1]. In contrast, atypical antipsychotic drugs such as clozapine exhibit a reduced risk of TD [2]. However, the neurochemical mechanisms that underlie the differential effects between typical and atypical antipsychotic drugs on TD remain unclear [3]. Abnormalities in dopaminergic function, specifically, the supersensitivity of dopamine (DA) receptors, have been demonstrated to involved in the pathophysiology of TD [4]. Behavioral evidence of dopamine hypersensitivity is convinced in many different animal models. The up-regulation of D2 dopamine receptors was thought to be the primary mechanism responsible for the development of behavioral sensitivity [4]. Apomorphine (APO), a nonselective D1/D2 agonist, can induce stereotyped behavior and vacuous chewing movements (VCMs) following chronic treatment with neuroleptics and routinely has been used as an experimental model of TD [5]. Aquaporin-4 (AQP4), a predominant water channel in brain, is highly expressed in perivascular astrocyte endfeet and plays crucial roles in central nervous system [6]. AQP4 knockout increases DA synthesis and turnover in various brain regions. Currently, multiple lines of evidence suggest that AQP4 is involved in anomalous dopaminergic neurotransmission-induced diseases, such as Parkinson’s disease [7], addiction [8] and mood disorders. However, the implication of AQP4 in TD remains unclear. In the present study, AQP4 knockout mice (AQP4 / ) were applied to define the roles of AQP4 in TD. Twelve-week-old male AQP4 and AQP4 / mice were injected with haloperidol (2 mg/kg i.p.), clozapine (10 mg/kg i.p.), or saline once a day for 21 days. Locomotor activities were monitored after the final injections by using ZIL-2 activity meter (Chinese Academy of Medical Sciences). Mice were placed into activity monitor chambers (20 cm 9 20 cm) for 10 min, and then activities were measured at 10-min intervals. Subsequently, mice received an injection of APO (1 mg/kg, s.c.). Following this injection, the numbers of activities were recorded for the next 10-min intervals. As shown in Figure 1, both haloperidol and clozapine showed a significant inhibitory effect on locomotor activities in AQP4 and AQP4 / mice. The typical antipsychotic haloperidol was much more potent in inhibiting locomotor activity than the atypical antipsychotic clozapine in both genotypes of mice (Figure 1A). AQP4 knockout did not influence these behavioral differences in locomotor activity. AQP4 mice displayed marked hyperlocomotion after APO-stimulation. Notably, AQP4 knockout abolished APO-induced hyperlocomotion following both chronic neuroleptics and saline treatment (Figure 1B). The results indicate that AQP4 knockout may directly block psychomotor stimulant action of APO. Vacuous chewing movements induced by a long-term neuroleptic administration in rodent animals have been the most extensively used phenomenological animal model of TD[5]. VCMs were referred to as single mouth openings in the vertical plane not directed toward physical material. The numbers of VCMs were counted three days after the final injections. Mice were placed individually into clear observation cages (16 cm 9 30 cm 9 19 cm) without food for a 1-hour habituation period. VCMs were measured in 5-min intervals 5 min after the injection of APO (1 mg/kg, s.c.). We found AQP4 mice that stimulated by APO displayed a significant increase in VCMs in haloperidol pretreated group, but not in clozapine pretreated group. However, no change of VCMs in respond to APO was observed in AQP4 / mice following treated with haloperidol, clozapine or