Adenosinergic modulation of the discriminative-stimulus effects of methamphetamine in rats
Adenosinergic modulation of the discriminative-stimulus effects of methamphetamine in rats
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DOI：
10.1007/s00213-002-1075-5
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发表时间：
2002-06-01
影响因子：
3.4
通讯作者：
Goldberg, SR
中科院分区：
文献类型：
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作者：
Munzar, P;Justinova, Z;Goldberg, SR
基本原理：A（1）和A（2A）腺苷受体分别与多巴胺D-1和D-2受体共定位，它们的刺激减弱多巴胺能功能。目的：测试对A（1）和A（2A）受体具有不同选择性的腺苷拮抗剂是否模拟多巴胺受体阻断剂甲基苯丙胺的辨别刺激效应。研究方法：在Sprague-Dawley大鼠中评价了A（1）拮抗剂DPCPX、优先A（2A）拮抗剂DMPX和非选择性腺苷拮抗剂咖啡因的作用，这些大鼠在固定比例10的食物呈现时间表下接受了区分1.0 mg/kg（IP）甲基苯丙胺和盐水的训练。结果：A（1）受体拮抗剂DPCPX（1.0- 10.0mg/kg）不能替代甲基苯丙胺。然而，5.6 mg/kg DPCPX使甲基苯丙胺剂量-反应曲线向左移动。在最高试验剂量下，A（2A）拮抗剂DMPX（1.8-18.0 mg/kg）产生约70%的甲基苯丙胺适当应答，非选择性拮抗剂咖啡因（3.0-56.0 mg/kg）产生约50%的甲基苯丙胺适当应答。DMPX（5.6 mg/kg）和咖啡因（30.0 mg/kg）均使甲基苯丙胺剂量-反应曲线向左移动。DMPX的甲基苯丙胺样作用被D-2拮抗剂螺哌隆（0.18 mg/kg）完全阻断，部分被D-1拮抗剂SCH-23390（0.018 mg/kg）阻断。结论：A（2A）腺苷受体的拮抗作用通过与多巴胺受体的相互作用直接模拟甲基苯丙胺的辨别刺激作用。腺苷A（1）受体的拮抗作用增强了低剂量甲基苯丙胺的作用，因此起着相当间接的调节作用。
Rationale: A(1) and A(2A) adenosine receptors are co-localized with dopamine D-1 and D-2 receptors, respectively, and their stimulation attenuates dopaminergic functioning. Objective: To test whether adenosine antagonists with different selectivities for A(1) and A(2A) receptors mimic the discriminative-stimulus effects of dopamine releaser methamphetamine. Methods: Effects of the A(1) antagonist DPCPX, the preferential A(2A) antagonist DMPX and the non-selective adenosine antagonist caffeine were evaluated in Sprague-Dawley rats trained to discriminate 1.0 mg/kg, IP, meth amphetamine from saline under a fixed-ratio 10 schedule of food presentation. Results: The A(1) antagonist DPCPX (1.0-10.0 mg/kg) failed to substitute for methamphetamine. However, 5.6 mg/kg DPCPX shifted the methamphetamine dose-response curve to the left. The A(2A) antagonist DMPX (1.8-18.0 mg/kg) produced about 70% methamphetamine-appropriate responding and the non-selective antagonist caffeine (3.0-56.0 mg/kg) about 50% methamphetamine-appropriate responding at the highest tested doses. Both DMPX (5.6 mg/kg) and caffeine (30.0 mg/kg) shifted the methamphetamine dose-response curve to the left. Methamphetamine-like effects of DMPX were blocked fully by the D-2 antagonist spiperone (0.18 mg/kg) and partially by the D-1 antagonist SCH-23390 (0.018 mg/kg). Conclusions: Antagonism at A(2A) adenosine receptors directly mimics the discriminative-stimulus effects of methamphetamine through the interaction with dopamine receptors. Antagonism at A(1) adenosine receptors potentiates effects of lower methamphetamine doses and thus plays a rather indirect, modulatory role.