Li Y, Wolf M E
Department of Neuroscience, Finch University of Health Sciences/The Chicago Medical School, North Chicago, IL 60064, USA.
Psychopharmacology (Berl). 1999 Feb;141(4):351-61. doi: 10.1007/s002130050844.
Many laboratories have reported that coadministration of N-methyl-D-aspartate (NMDA) receptor antagonists with psychomotor stimulants prevents the development of behavioral sensitization and therefore concluded that NMDA receptor transmission is necessary for sensitization. According to an alternative "state-dependency" interpretation, NMDA receptor antagonists do not prevent sensitization. Rather, they become a conditioned stimulus for the sensitized response, i.e., it is only elicited in response to combined administration of the NMDA receptor antagonist and the stimulant. This hypothesis is supported by progressive augmentation of the locomotor response to the drug combination during the induction phase, and expression of sensitization when challenged with the combination but not the stimulant alone. To test this hypothesis, rats were treated during a 6-day induction phase with amphetamine (Amph) alone or in combination with the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg) or the non-competitive NMDA receptor antagonist MK-801 (0.05, 0.1 and 0.25 mg/kg). When CGS 19755 was coadministered with Amph, there was no progressive augmentation of response to the drug combination. When challenged with Amph alone, rats did not exhibit the biphasic pattern of locomotor activity characteristic of Amph sensitization. No sensitization of stereotyped behaviors was evident, although the ambulatory response was greater than that exhibited by naive rats. Results with MK-801 were complex, but progressive augmentation of response to the drug combination appeared to in part reflect sensitization to MK-801 and could be dissociated from the ability of MK-801 to prevent the development of sensitization as assessed by response to challenge with Amph alone. Many of these findings are inconsistent with predictions of the "state-dependency" hypothesis. Moreover, the ability of NMDA receptor antagonists to prevent biochemical and electrophysiological correlates of sensitization is difficult to reconcile with the idea that sensitization develops in the presence of NMDA receptor blockade but cannot be expressed. Together, these findings suggest that the ability of NMDA receptor antagonists to prevent Amph sensitization reflects a requirement for NMDA receptor transmission during its induction.
许多实验室报告称，将N-甲基-D-天冬氨酸（NMDA）受体拮抗剂与精神运动性兴奋剂共同给药可防止行为敏化的发展，因此得出结论，NMDA受体传递是敏化所必需的。根据另一种“状态依赖性”解释，NMDA受体拮抗剂并不能防止敏化。相反，它们成为敏化反应的条件刺激，即只有在NMDA受体拮抗剂和兴奋剂联合给药时才会引发该反应。这一假设得到了诱导期对药物组合的运动反应逐渐增强以及用该组合而非单独的兴奋剂激发时敏化表达的支持。为了验证这一假设，在为期6天的诱导期内，用苯丙胺（Amph）单独或与竞争性NMDA受体拮抗剂CGS 19755（10mg/kg）或非竞争性NMDA受体拮抗剂MK-801（0.05、0.1和0.25mg/kg）联合处理大鼠。当CGS 19755与Amph共同给药时，对药物组合的反应没有逐渐增强。当单独用Amph激发时，大鼠没有表现出Amph敏化特征性的双相运动活动模式。虽然走动反应大于未处理大鼠，但刻板行为没有明显的敏化现象。MK-801的结果较为复杂，但对药物组合的反应逐渐增强似乎部分反映了对MK-801的敏化，并且可以与MK-801防止敏化发展的能力（通过单独用Amph激发的反应评估）区分开来。这些发现中有许多与“状态依赖性”假设的预测不一致。此外，NMDA受体拮抗剂防止敏化的生化和电生理相关指标的能力，很难与敏化在NMDA受体阻断存在时发展但无法表达的观点相协调。总之，这些发现表明，NMDA受体拮抗剂防止Amph敏化的能力反映了诱导过程中对NMDA受体传递的需求。
