Grönig M, Atalla A, Kuschinsky K
Institute of Pharmacology and Toxicology, Faculty of Pharmacy, University of Marburg, Ketzerbach 63, 35032 Marburg, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2004 Feb;369(2):228-31. doi: 10.1007/s00210-003-0855-8. Epub 2003 Dec 12.
Blockade of glutamate receptors of the NMDA type inhibits the sensitization to psychostimulant drugs, such as amphetamine, that occurs after repeated administration. Both associative (conditioning) and non-associative (pseudo-conditioning) mechanisms may contribute to sensitization phenomena. The aim of the present study was, thus, to determine which type of sensitization is influenced by blockade of NMDA-type receptors by examining the expression (manifestation) of sensitization. Locomotor activity was assessed and, in some experiments, extracellular dopamine in the nucleus accumbens was also assessed using in vivo microdialysis in non-anaesthetized, almost freely moving rats. Male albino Wistar rats of 225-250 g were given 1 mg/kg i.p. d-amphetamine every 2nd day for 7 days and with saline on the other days. Half the rats were exposed to d-amphetamine in the presence of conditioning stimuli (test cage, auditory and olfactory stimulus) and to saline in the home cage in absence of these stimuli, the other half were treated with saline and exposed to the conditioning stimuli and were placed into their home cages (without conditioning stimuli) after treatment with d-amphetamine. Ten days after the end of this treatment, both groups were exposed to the conditioning stimuli and half of each group were pretreated with dizocilpine [(+)-MK-801, 0.1 mg/kg i.p.], a blocker of NMDA receptors, 30 min before administration of 1 mg/kg d-amphetamine. (+)-MK-801 reduced the locomotor activity in rats sensitized associatively, but not in those sensitized non-associatively. It had no significant effect on spontaneous locomotor activity or that induced by acute administration of 1 mg/kg d-amphetamine. Similarly, (+)-MK-801 inhibited the increase in extracellular dopamine in the nucleus accumbens induced by the test dose of d-amphetamine in rats sensitized associatively but not non-associatively. The results suggest that the expression of both types of sensitization to d-amphetamine are dependent on glutamatergic NMDA mechanisms, although in different ways. Inhibition of sensitization, in particular of the associative type, might be of therapeutic value in drug dependence.
阻断N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体可抑制对精神兴奋药物（如苯丙胺）的敏化作用，这种敏化作用在反复给药后会出现。联合（条件作用）和非联合（假条件作用）机制都可能导致敏化现象。因此，本研究的目的是通过检查敏化作用的表达（表现）来确定哪种类型的敏化作用受NMDA型受体阻断的影响。评估了动物的运动活性，并且在一些实验中，还使用体内微透析技术在未麻醉、几乎自由活动的大鼠中评估了伏隔核中的细胞外多巴胺水平。给体重225 - 250 g的雄性白化Wistar大鼠每隔一天腹腔注射1 mg/kg的右旋苯丙胺，共注射7天，其他日子注射生理盐水。一半的大鼠在有条件刺激（测试笼、听觉和嗅觉刺激）的情况下接触右旋苯丙胺，在没有这些刺激的家笼中接触生理盐水；另一半大鼠用生理盐水处理，并暴露于条件刺激下，在用右旋苯丙胺处理后放入它们的家笼（没有条件刺激）。在这种处理结束10天后，两组大鼠都暴露于条件刺激下，并且每组中的一半在给予1 mg/kg右旋苯丙胺前30分钟用NMDA受体阻断剂地佐环平[（+）-MK-801，0.1 mg/kg腹腔注射]进行预处理。（+）-MK-801降低了联合致敏大鼠的运动活性，但对非联合致敏大鼠没有影响。它对自发运动活性或急性给予1 mg/kg右旋苯丙胺诱导的运动活性没有显著影响。同样，（+）-MK-801抑制了联合致敏但非联合致敏大鼠中测试剂量的右旋苯丙胺诱导的伏隔核细胞外多巴胺的增加。结果表明，对右旋苯丙胺的两种类型的敏化作用的表达都依赖于谷氨酸能NMDA机制，尽管方式不同。抑制敏化作用，特别是联合型敏化作用，可能在药物依赖方面具有治疗价值。
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