Inactivation of adenosine A2A receptors selectively attenuates amphetamine-induced behavioral sensitization
Inactivation of adenosine A2A receptors selectively attenuates amphetamine-induced behavioral sensitization
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DOI：
10.1038/sj.npp.1300152
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发表时间：
2003-06-01
影响因子：
7.6
通讯作者：
Schwarzschild, MA
中科院分区：
文献类型：
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作者：
Chen, JF;Moratalla, R;Schwarzschild, MA
反复使用精神兴奋剂安非他明会产生行为致敏，这可能代表了人类精神病和成瘾的某些特征背后的神经适应。在本研究中，我们使用A（2A）受体敲除（A(2A) KO）模型研究了腺苷A（2A）受体在精神兴奋剂诱导的运动致敏中的作用。每天服用安非他明1周后，第8天的运动反应增强（与第1天相比增强了两倍），并且在第24天再次服用安非他明后，运动反应仍然增强。相比之下，A(2A) KO小鼠在第8天或第24天没有出现对每日安非他明的运动致敏，这种缺失不是非特异性阈值效应的结果。安非他明没有行为致敏是选择性的，因为每天使用D-1激动剂SKF81297 （2.5 mg/kg）或D-2激动剂quinpirole （1.0mg/kg）在WT和A(2A) KO小鼠中产生相似的行为致敏。此外，SKF81297和喹匹罗联合注射也导致A(2A) KO和WT小鼠的运动致敏，这表明D-1和D-2受体反应正常。最后，在细胞水平上，A（2A）受体失活消除了反复服用安非他明引起的纹状体肌啡肽mRNA的增加。在A(2A) KO小鼠中，安非他明诱导的行为致敏选择性缺失表明，A（2A）受体在精神兴奋剂诱导的行为致敏发展中起着关键作用，并支持A（2A）腺苷能药物调节反复暴露于精神兴奋剂的适应性反应的药理潜力。
Repeated treatment with the psychostimulant amphetamine produces behavioral sensitization that may represent the neural adaptations underlying some features of psychosis and addiction in humans. In the present study we investigated the role of adenosine A(2A) receptors in psychostimulant-induced locomotor sensitization using an A(2A) receptor knockout (A(2A) KO) model. Daily treatment with amphetamine for 1 week resulted in an enhanced motor response on day 8 (by two-fold compared to that on day 1), and remained enhanced at day 24 upon rechallenge with amphetamine. By contrast, locomotor sensitization to daily amphetamine did not develop in A(2A) KO mice on day 8 or 24, and this absence was not the result of a nonspecific threshold effect. The absence of behavioral sensitization was selective for amphetamine since daily treatment with the D-1 agonist SKF81297 (2.5 mg/kg) or the D-2 agonist quinpirole (1.0mg/kg) produced similar behavioral sensitization in both WT and A(2A) KO mice. Furthermore, coinjection of SKF81297 and quinpirole also resulted in indistinguishable locomotor sensitization in A(2A) KO and WT mice, suggesting normal D-1 and D-2 receptor responsiveness. Finally, at the cellular level A(2A) receptor inactivation abolished the increase in striatal dynorphin mRNA induced by repeated amphetamine administration. The selective absence of amphetamine-induced behavioral sensitization in A(2A) KO mice suggests a critical role of the A(2A) receptor in the development of psychostimulant-induced behavioral sensitization, and supports the pharmacological potential of A(2A) adenosinergic agents to modulate adaptive responses to repeated psychostimulant exposure.