Persistent behavioral sensitization to chronic L-DOPA requires A2A adenosine receptors
Persistent behavioral sensitization to chronic L-DOPA requires A2A adenosine receptors
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DOI：
10.1523/jneurosci.22-03-01054.2002
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发表时间：
2002-02-01
影响因子：
5.3
通讯作者：
Chen, JF
中科院分区：
文献类型：
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作者：
Fredduzzi, S;Moratalla, R;Chen, JF
为了研究 A(2A) 腺苷受体在对慢性间歇性多巴胺受体刺激的适应性反应中的作用，我们比较了半帕金森病野生型 (WT) 和 A(2A) 腺苷受体敲除 (A(2A) KO) 小鼠重复左旋多巴治疗引起的行为敏化。尽管纹状体内注射6-羟基多巴胺产生的单侧黑质纹状体损伤在WT和A(2A) KO小鼠之间无法区分，但在每天用低剂量的L-DOPA治疗3周后，它们出现了显着不同的行为敏化模式。 WT 小鼠最初表现出适度的对侧旋转反应，然后逐渐产生更大的反应，在 1 周内达到最大值，并在治疗期间持续存在。相比之下，A(2A) KO 小鼠中的任何旋转行为敏化都是短暂的，并在 2 周内完全逆转。同样，WT 小鼠中达到峰值旋转的时间逐渐缩短，但 A(2A) KO 小鼠中保持不变。此外，每日L-DOPA治疗使WT小鼠逐渐产生敏化梳理行为，但未能在A(2A) KO小鼠中诱导任何敏化梳理行为。最后，重复的L-DOPA治疗在WT小鼠中逆转了6-OHDA诱导的纹状体强啡肽mRNA的减少，但在A(2A) KO小鼠中没有逆转，这提高了A(2A)受体可能通过促进表达强啡肽的纹状体黑质通路内的适应而有助于L-DOPA诱导的行为敏化的可能性。这些结果共同表明，A(2A) 受体在发展中发挥着关键作用，尤其是对重复左旋多巴治疗的行为敏感性的持久性。此外，他们还提出了一种可能性，即帕金森病患者对长期 L-DOPA 治疗的适应不良运动障碍反应可能会因 A(2A) 受体失活而减弱。
To investigate the role of A(2A) adenosine receptors in adaptive responses to chronic intermittent dopamine receptor stimulation, we compared the behavioral sensitization elicited by repeated L-DOPA treatment in hemiparkinsonian wild-type (WT) and A(2A) adenosine receptor knock-out (A(2A) KO) mice. Although the unilateral nigrostriatal lesion produced by intrastriatal injection of 6-hydroxydopamine was indistinguishable between WT and A(2A) KO mice, they developed strikingly different patterns of behavioral sensitization after daily treatment with low doses of L-DOPA for 3 weeks. WT mice initially displayed modest contralateral rotational responses and then developed progressively greater responses that reached a maximum within 1 week and persisted for the duration of the treatment. In contrast, any rotational behavioral sensitization in A(2A) KO mice was transient and completely reversed within 2 weeks. Similarly, the time to reach the peak rotation was progressively shortened in WT mice but remained unchanged in A(2A) KO mice. Furthermore, daily L-DOPA treatment produced gradually sensitized grooming in WT mice but failed to induce any sensitized grooming in A(2A) KO mice. Finally, repeated L-DOPA treatment reversed the 6-OHDA-induced reduction of striatal dynorphin mRNA in WT but not A(2A) KO mice, raising the possibility that the A(2A) receptor may contribute to L-DOPA-induced behavioral sensitization by facilitating adaptations within the dynorphin-expressing striatonigral pathway. Together these results demonstrate that the A(2A) receptor plays a critical role in the development and particularly the persistence of behavioral sensitization to repeated L-DOPA treatment. Furthermore, they raise the possibility that the maladaptive dyskinetic responses to chronic L-DOPA treatment in Parkinson's disease may be attenuated by A(2A) receptor inactivation.