Ranaldi R, Munn E, Neklesa T, Wise R A
Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Quebec, Canada.
Psychopharmacology (Berl). 2000 Aug;151(2-3):192-201. doi: 10.1007/s002130000480.
It has been inferred from indirect tests that MK-801, an NMDA receptor antagonist, blocks sensitization to amphetamine and to morphine. These inferences were made from studies where behavioral scores were not recorded after each drug treatment in the sensitization protocol.
We reinvestigated the role of NMDA receptors in sensitization to amphetamine or morphine more directly by taking locomotor and stereotypy scores after each of several treatments with MK-801 and amphetamine or morphine.
Each male Long Evans rat was administered intraperitoneal injections of MK-801 (0.1 or 0.25 mg/kg) or saline followed 30 minutes later by amphetamine (0.75 mg/kg), morphine (1.25 mg/kg) or saline and placed immediately in a photocell chamber. Locomotion and stereotypy were measured simultaneously by photobeam breaks and direct observation, respectively. This procedure was repeated on days 1, 2, 3, 4, 5, 8, 11 and 27 for rats receiving amphetamine or saline as the second injection and on days 1-10, 13, 16 and 32 for rats receiving morphine or saline as their second injection (with no testing or treatment on intervening days).
The animals treated in the amphetamine condition and animals treated in the morphine condition all showed progressively greater locomotion and stereotypy over the first 5 (amphetamine) or 10 (morphine) test days; the sensitized response was seen regardless of whether the animals were pretreated with saline or with MK-801. Thus MK-801 failed to block the development of psychomotor sensitization seen with these treatment regimens. When, following initial sensitization, amphetamine or morphine was given in the absence of MK-801 (days 8 and 13 for amphetamine and morphine rats, respectively), there was no expression of the sensitized response; the sensitized response of animals previously treated in the MK-801 drug state was expressed only when the animal was tested in the MK-801 drug state. The sensitized response was still expressed, in animals tested in the appropriate drug condition, after a 2-week period in which no drugs were given, confirming that the changes underlying this form of sensitization were long-lasting and thus probably a consequence of some form of synaptic plasticity.
Our data provide evidence that behavioral sensitization to amphetamine and to morphine can occur despite the presence of NMDA receptor blockade. These and previous findings suggest that the failure of expression of sensitization seen when MK-801 is withdrawn from a given psychomotor stimulant treatment regimen reflects, at least in part, the dependency of sensitization on the various conditions of training rather than dependency on some essential function of NMDA receptor activation.
从间接试验推断，NMDA受体拮抗剂MK-801可阻断对苯丙胺和吗啡的敏化作用。这些推断是基于敏化实验方案中未在每次药物治疗后记录行为评分的研究得出的。
我们通过在多次给予MK-801和苯丙胺或吗啡治疗后记录运动和刻板行为评分，更直接地重新研究了NMDA受体在对苯丙胺或吗啡敏化中的作用。
给每只雄性长 Evans 大鼠腹腔注射MK-801（0.1或0.25mg/kg）或生理盐水，30分钟后注射苯丙胺（0.75mg/kg）、吗啡（1.25mg/kg）或生理盐水，然后立即放入光电管箱中。分别通过光束中断和直接观察同时测量运动和刻板行为。接受苯丙胺或生理盐水作为第二次注射的大鼠在第1、2、3、4、5、8、11和27天重复此过程，接受吗啡或生理盐水作为第二次注射的大鼠在第1至10、13、16和32天重复此过程（中间天数不进行测试或治疗）。
接受苯丙胺治疗的动物和接受吗啡治疗的动物在最初的5天（苯丙胺）或10天（吗啡）测试中均表现出逐渐增强的运动和刻板行为；无论动物预先用生理盐水还是MK-801预处理，均出现敏化反应。因此，MK-801未能阻断这些治疗方案中出现的精神运动敏化的发展。在最初敏化后，当在没有MK-801的情况下给予苯丙胺或吗啡时（苯丙胺和吗啡大鼠分别在第8天和第13天），未出现敏化反应；先前在MK-801药物状态下治疗的动物的敏化反应仅在动物处于MK-801药物状态下进行测试时才表现出来。在停药2周后，在适当药物条件下测试的动物仍表现出敏化反应，这证实了这种形式的敏化所涉及的变化是持久的，因此可能是某种形式的突触可塑性的结果。
我们的数据表明，尽管存在NMDA受体阻断，对苯丙胺和吗啡的行为敏化仍可能发生。这些以及先前的研究结果表明，当从给定的精神运动兴奋剂治疗方案中撤去MK-801时，敏化反应表达失败至少部分反映了敏化对各种训练条件的依赖性，而不是对NMDA受体激活某些基本功能的依赖性。
