Adenosine A2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A2A receptor antagonists has shown a significant improvement of the effects of l-DOPA. The present review emphasizes the possible application of A2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A2A receptors. A2A)receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A2A receptor knockout mice suggest that A2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.

译文

位于背侧纹状体的腺苷A2A受体被认为是开发抗帕金森病药物的新靶标。A2A受体拮抗剂的共同给药显示了l-多巴的作用的显着改善。本综述强调了A2A受体拮抗剂在帕金森氏症以外的其他病理疾病 (包括药物成瘾,睡眠障碍和疼痛) 中的可能应用。除背侧纹状体外,腹侧纹状体 (伏隔核) 还包含高密度的A2A受体,其突触前和突触后调节皮质谷氨酸能投射到伏隔核的谷氨酸能传递。目前认为,皮质伏隔肌谷氨酸能突触的分子适应与强迫性药物寻找和复发有关。在这里,我们回顾了最近的实验证据,表明A2A拮抗剂可能成为药物成瘾的新治疗剂。形态学和功能研究已经确定了除纹状体以外的大脑区域中较低水平的A2A受体,例如下丘脑的腹外侧视前区,其中腺苷在睡眠调节中起着重要作用。尽管最初认为主要依赖于A1受体,但我们在这里回顾了最近的研究,这些研究表明,腺苷的促睡眠作用主要由下丘脑A2A受体介导。因此,A2A) 受体拮抗剂可以被认为是发作性睡病和其他睡眠相关疾病的可能治疗方法。最后,伤害感受是另一种腺苷调节的神经功能,以前被认为主要涉及A1受体。尽管关于激动剂和拮抗剂的作用存在一些相互矛盾的文献,这可能部分是由于缺乏可用药物的选择性,但对A2A受体敲除小鼠的研究表明,A2A受体拮抗剂在疼痛状态下可能具有一定的治疗潜力,特别是在高强度刺激普遍存在的地方。

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