Dravolina O A, Medvedev I O, Bespalov A Y
Laboratory of Behavioural Pharmacology, Valdman Institute of Pharmacology, Pavlov Medical University, St Petersburg, Russia.
Behav Pharmacol. 1999 Jul;10(4):359-66. doi: 10.1097/00008877-199907000-00003.
Glutamate receptors are implicated in the development and expression of drug dependence. Substantial experimental evidence suggests that antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors attenuate the severity of opioid withdrawal. However, it is less clear whether opioid withdrawal can be potentiated by agonists of glutamate receptors. The present study evaluated the behavioural effects of various agonists of glutamate receptors, as well as a nitric oxide (NO) donor, in morphine-dependent rats trained to discriminate 0.1 mg/kg of naloxone from saline. None of the following drugs produced appreciable levels of naloxone-like responding (substitution tests) or potentiated the discriminative stimulus effects of naloxone: NMDA (3-56 mg/kg), glycine (100-1000 mg/kg), glutamate (1000-3000 mg/kg), kainate (0.3-3 mg/kg), isosorbide dinitrate (30-300 mg/kg). Nevertheless, expression of some morphine withdrawal-like somatic and behavioural signs ('wet-dog'-like shaking, scream on touch, ptosis, tremor, chewing, weight loss) was facilitated by NMDA, glycine, and isosorbide dinitrate. These results suggest that, compared to somatic symptoms, subjective effects of opioid withdrawal (as reflected by discriminative stimulus effects) are not mimicked by direct activation of glutamate receptors.
谷氨酸受体与药物依赖的形成和表现有关。大量实验证据表明，作用于谷氨酸受体N-甲基-D-天冬氨酸（NMDA）亚型的拮抗剂可减轻阿片类药物戒断的严重程度。然而，谷氨酸受体激动剂是否能增强阿片类药物戒断反应尚不清楚。本研究评估了谷氨酸受体各种激动剂以及一氧化氮（NO）供体对训练区分0.1mg/kg纳洛酮和生理盐水的吗啡依赖大鼠的行为影响。以下药物均未产生明显水平的纳洛酮样反应（替代试验）或增强纳洛酮的辨别刺激效应：NMDA（3 - 56mg/kg）、甘氨酸（100 - 1000mg/kg）、谷氨酸（1000 - 3000mg/kg）、红藻氨酸（0.3 - 3mg/kg）、硝酸异山梨酯（30 - 300mg/kg）。然而，NMDA、甘氨酸和硝酸异山梨酯促进了一些类似吗啡戒断的躯体和行为体征（“湿狗”样颤抖、触摸时尖叫、上睑下垂、震颤、咀嚼、体重减轻）的表现。这些结果表明，与躯体症状相比，谷氨酸受体直接激活不能模拟阿片类药物戒断的主观效应（由辨别刺激效应反映）。
