Fredriksson A, Archer T
Department of Neuroscience, University of Uppsala, Uppsala, Sweden.
Amino Acids. 2002;23(1-3):111-32. doi: 10.1007/s00726-001-0117-3.
Antiakinsic effects of the uncompetitive NMDA antagonists, memantine, amantadine and MK-801, and competitive antagonists, CGP 40116, alone or in co-administration with acute subthreshold dose of L-Dopa (5 mg/kg) in MPTP-treated mice, functional alterations induced by acute MK-801 in combinations with neuroleptic compounds or behavioural deficits following postnatal administration of MK-801 were investigated. Memantine and amantadine injected 60 min before the subthreshold dose of L-Dopa (5 mg/kg), induced antiakinesic actions in hypokinesic MPTP-treated mice. Concurrently, higher doses of memantine and MK-801 caused dyskinesic changes, reducing further rearing (10 and 30 mg/kg) and locomotor (30 mg/kg) behaviour of the MPTP mice; MK-801 elevated locomotion (0.1 mg/kg) but reduced rearing (0.3 mg/kg). In control, saline-treated mice, memantine (3, 10 and 30 mg/kg) and MK-801 (0.1 and 0.3 mg/kg) increased locomotor behaviour but decreased rearing behaviour. In rats, MK-801 induced marked increases in locomotor activity and disruptions of circular swim maze acquisition that were to greater or lesser extents blocked or potentiated by neuroleptic compounds: SCH 23390 (0.005 and 0.05 mg/kg) and clozapine (5.0 and 10.0 mg/kg) dose-dependently antagonised MK-801 (0.3 mg/kg) induced locomotor activity whereas raclopride (0.1 mg/kg) and haloperidol (0.1 mg/kg) attenuated it dose-specifically. Amperozide (0.5 mg/kg) attenuated the MK-801 effect but potentiated it at the 2.0 mg/kg dose. In the circular swim maze, raclopride (0.01 mg/kg) and SCH 23390 (0.05 mg/kg) improved the acquisitive performance of rats administered MK-801 (0.03 mg/kg) acutely whereas clozapine (10.0 mg/kg) and amperozide (2.0 mg/kg) deteriorated the performance of MK-801-treated rats. Postnatal administration of MK-801 (0.05 mg/kg, day 11 after birth) induced severe functional alterations in adult mice. At 70 days of age, MK-801 mice showed an initial hypoactivity followed by marked hyperactivity in the motor activity test chambers. These mice showed deficits in habituation, a nonassociative form of learning. Their hyperactivity in the test chambers was reversed by a low dose of d-amphetamine (0.25 mg/kg). Taken together, these findings display a wide range of acute/long-term functional alterations induced by NMDA antagonists, particularly MK-801, associated with animal models of brain disorders.
研究了非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂美金刚、金刚烷胺和MK-801以及竞争性拮抗剂CGP 40116单独使用或与急性阈下剂量左旋多巴（5mg/kg）联合使用对MPTP处理小鼠的抗运动不能作用，急性MK-801与抗精神病化合物联合使用引起的功能改变或出生后给予MK-801后的行为缺陷。在阈下剂量左旋多巴（5mg/kg）前60分钟注射美金刚和金刚烷胺，可在运动不能的MPTP处理小鼠中诱导抗运动不能作用。同时，较高剂量的美金刚和MK-801引起运动障碍性改变，进一步降低MPTP小鼠的竖毛行为（10和30mg/kg）和运动行为（30mg/kg）；MK-801增加运动（0.1mg/kg）但减少竖毛行为（0.3mg/kg）。在对照的生理盐水处理小鼠中，美金刚（3、10和30mg/kg）和MK-801（0.1和0.3mg/kg）增加运动行为但减少竖毛行为。在大鼠中，MK-801诱导运动活动显著增加并破坏环形游泳迷宫习得，抗精神病化合物在不同程度上阻断或增强了这些作用：SCH 23390（0.005和0.05mg/kg）和氯氮平（5.0和10.0mg/kg）剂量依赖性地拮抗MK-801（0.3mg/kg）诱导的运动活动，而雷氯必利（0.1mg/kg）和氟哌啶醇（0.1mg/kg）特异性地减弱其作用。氨哌齐特（0.5mg/kg）减弱MK-801的作用，但在2.0mg/kg剂量时增强其作用。在环形游泳迷宫中，雷氯必利（0.01mg/kg）和SCH 23390（0.05mg/kg）改善了急性给予MK-801（0.03mg/kg）大鼠的习得性能，而氯氮平（10.0mg/kg）和氨哌齐特（2.0mg/kg）则使MK-801处理大鼠的性能恶化。出生后给予MK-801（0.05mg/kg，出生后第11天）可在成年小鼠中诱导严重的功能改变。在70日龄时，MK-801小鼠在运动活动测试箱中最初表现为活动减少，随后出现明显的活动过度。这些小鼠在习惯化方面存在缺陷，习惯化是一种非联想性学习形式。它们在测试箱中的活动过度可被低剂量的右旋苯丙胺（0.25mg/kg）逆转。综上所述，这些发现显示了NMDA拮抗剂，特别是MK-801，在与脑部疾病动物模型相关的情况下诱导的广泛急性/长期功能改变。
