Chen Jiang-Fan, Moratalla Rosario, Yu Liqun, Martín Ana B, Xu Kui, Bastia Elena, Hackett Elizabeth, Alberti Israel, Schwarzschild Michael A
Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston 02129, USA.
Neuropsychopharmacology. 2003 Jun;28(6):1086-95. doi: 10.1038/sj.npp.1300152. Epub 2003 Apr 9.
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 (1.0 mg/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.
用精神兴奋剂苯丙胺反复治疗会产生行为敏化，这可能代表了人类精神病和成瘾某些特征背后的神经适应性变化。在本研究中，我们使用A(2A)受体基因敲除(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敏化中的作用。每天用苯丙胺治疗1周，导致第8天运动反应增强(与第1天相比增加了两倍)，并且在第24天再次用苯丙胺激发时仍保持增强。相比之下，A(2A) KO小鼠在第8天或第24天对每日苯丙胺未产生运动敏化，且这种缺失并非非特异性阈值效应的结果。行为敏化的缺失对苯丙胺具有选择性，因为每天用D(1)激动剂SKF81297(2.5mg/kg)或D(2)激动剂喹吡罗(1.0mg/kg)治疗在野生型和A(2A) KO小鼠中均产生了类似的行为敏化。此外，同时注射SKF81297和喹吡罗在A(2A) KO和野生型小鼠中也导致了难以区分的运动敏化，表明D(1)和D(2)受体反应性正常。最后，在细胞水平上，A(2A)受体失活消除了反复给予苯丙胺所诱导的纹状体强啡肽mRNA的增加。A(2A) KO小鼠中选择性缺乏苯丙胺诱导的行为敏化表明A(2A)受体在精神兴奋剂诱导的行为敏化发展中起关键作用，并支持A(2A)腺苷能药物调节对反复精神兴奋剂暴露的适应性反应的药理学潜力。
