St-Pierre J A, Bédard P J
Department of Pharmacology, Laval University, Québec, Canada.
Eur J Pharmacol. 1995 Jan 16;272(2-3):123-9. doi: 10.1016/0014-2999(94)00612-b.
Systemic administration of the non-competitive antagonist of NMDA receptors MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) potentiates the circling response induced by direct stimulation of the striatal dopaminergic receptors through intracerebral application of dopamine. Microinjection of dopamine (1, 5, 25 or 50 micrograms/1.0 microliters) induced a dose-dependent contralateral circling response, when injected directly into the lesioned side of unilaterally 6-hydroxydopamine-lesioned rats. Interestingly, intrastriatal application of dopamine (1, 5, 25 or 50 micrograms/1.0 microliters) followed by a systemic administration of MK-801 (100 micrograms/kg i.p.) produced a potentiated contralateral circling response in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. This motor effect is reversed compared to the marked ipsilateral circling response produced by MK-801 when given alone. Moreover, the potentiated responses persist 4-fold longer compared to the circling induced by dopamine alone. The results suggest that the potentiation by NMDA receptor antagonists of motor activity induced by dopaminergic agonists in animal models of Parkinson's disease cannot be ascribed simply to increased release of dopamine. Other mechanisms including increased sensitivity of dopamine D1 receptors or blockade or glutamatergic transmission in output structures must be considered.
NMDA受体的非竞争性拮抗剂MK-801（(+)-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺）的全身给药通过脑内应用多巴胺增强了直接刺激纹状体多巴胺能受体所诱导的转圈反应。当将多巴胺（1、5、25或50微克/1.0微升）直接注射到单侧6-羟基多巴胺损伤大鼠的损伤侧时，会诱导出剂量依赖性的对侧转圈反应。有趣的是，在单侧6-羟基多巴胺（6-OHDA）损伤的大鼠中，纹状体内应用多巴胺（1、5、25或50微克/1.0微升）后全身给予MK-801（100微克/千克腹腔注射）会产生增强的对侧转圈反应。与单独给予MK-801时产生的明显同侧转圈反应相比，这种运动效应是相反的。此外，与单独由多巴胺诱导的转圈相比，增强的反应持续时间长4倍。结果表明，在帕金森病动物模型中，NMDA受体拮抗剂对多巴胺能激动剂诱导的运动活动的增强作用不能简单地归因于多巴胺释放的增加。必须考虑其他机制，包括多巴胺D1受体敏感性增加或输出结构中谷氨酸能传递的阻断。
