Effects of antipsychotic drugs on MK-801-induced attentional and motivational deficits in rats.
Effects of antipsychotic drugs on MK-801-induced attentional and motivational deficits in rats.
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DOI：
10.1016/j.neuropharm.2009.01.004
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发表时间：
2009-03
影响因子：
4.7
通讯作者：
Carlezon WA Jr
中科院分区：
文献类型：
--
作者：
Paine TA;Carlezon WA Jr
伴随精神分裂症的注意力缺陷不能通过现有的抗精神病药物有效治疗。NMDA受体功能的破坏通常用于在啮齿动物中模拟这种疾病的各个方面。我们使用5-选择系列反应时间任务（5CSRTT）来表征急性给药或从长期给药的NMDA受体拮抗剂MK-801撤出引起的注意力缺陷，并确定它们是否被氟哌啶醇或氯氮平改善。急性研究涉及在存在MK-801的情况下进行的试验：在每日试验前，对大鼠给予氟哌啶醇（0.008-0.125 mg/kg，SC）或氯氮平（0.16-2.5 mg/kg，SC）与MK-801（0.25 mg/kg，IP）联合给药。长期研究涉及在不存在MK-801的情况下进行的试验：每日试验后，对大鼠给予MK-801（0.5 mg/kg，IP），24小时后在不存在或存在氟哌啶醇或氯氮平的情况下进行试验。急性MK-801干扰性能：它降低了准确性，同时增加了遗漏，过早的反应，和杂志条目。氟哌啶醇减少了与激活增加相关的破坏性作用，而它加剧了其他缺陷。氯氮平剂量依赖性地减弱了几种MK-801诱导的表现缺陷。从长期MK-801中撤出逐渐增加遗漏和反应延迟，并减少过早反应，表明无动力状态。氟哌啶醇和氯氮平都不能改善这些表现缺陷。MK-801急性给药和长期停药在5CSRTT中产生了不同的行为特征。急性MK-801损害注意力和冲动控制，而慢性MK-801戒断引起与失动一致的体征。氟哌啶醇和氯氮平在减轻急性MK-801给药引起的缺陷方面更有效。
Attentional deficits that accompany schizophrenia are not effectively treated by available antipsychotic medications. Disruption of NMDA receptor function is often used to model aspects of this disorder in rodents. We used the 5-choice serial reaction time task (5CSRTT) to characterize attentional deficits caused by acute administration or withdrawal from chronic administration of the NMDA receptor antagonist MK-801, and determine if they are ameliorated by haloperidol or clozapine. Acute studies involved tests in the presence of MK-801: rats were administered haloperidol (0.008-0.125 mg/kg, SC) or clozapine (0.16-2.5 mg/kg, SC) in combination with MK-801 (0.25 mg/kg, IP) prior to daily test sessions. Chronic studies involved tests in the absence of MK-801: following daily tests, rats were administered MK-801 (0.5 mg/kg, IP) and tested 24 hr later in the absence or presence of haloperidol or clozapine. Acute MK-801 disrupted performance: it decreased accuracy while increasing omissions, premature responses, and magazine entries. Haloperidol reduced disruptive effects associated with increased activation, whereas it exacerbated other deficits. Clozapine dose-dependently attenuated several of the MK-801-induced performance deficits. Withdrawal from chronic MK-801 progressively increased omissions and response latencies and decreased premature responding, suggesting an amotivational state. Neither haloperidol nor clozapine ameliorated these performance deficits. Acute administration and withdrawal from chronic MK-801 administration produced distinct behavioral profiles in the 5CSRTT. Acute MK-801 impaired attention and impulse control whereas chronic MK-801 withdrawal caused signs consistent with amotivation. Haloperidol and clozapine were more effective at attenuating deficits caused by acute MK-801 administration.
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