Ferré S, Diamond I, Goldberg S R, Yao L, Hourani S M O, Huang Z L, Urade Y, Kitchen I
Preclinical Pharmacology Section, National Institute on Drug Abuse, Intramural Research Program, Department of Health and Human Services, Baltimore, MD 21224, USA.
Prog Neurobiol. 2007 Dec;83(5):332-47. doi: 10.1016/j.pneurobio.2007.04.002. Epub 2007 May 1.
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.
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点。联合使用A2A受体拮抗剂已显示出可显著改善左旋多巴的疗效。本综述强调了A2A受体拮抗剂在帕金森病以外的其他病理状况中的可能应用，包括药物成瘾、睡眠障碍和疼痛。除背侧纹状体外，腹侧纹状体（伏隔核）含有高密度的A2A受体，其在突触前和突触后调节皮质谷氨酸能投射至伏隔核中的谷氨酸能传递。目前认为，皮质-伏隔核谷氨酸能突触的分子适应性变化与强迫性觅药行为和复发有关。在此，我们综述了最近的实验证据，表明A2A拮抗剂可能成为治疗药物成瘾的新型治疗药物。形态学和功能研究已确定在纹状体以外的脑区，如下丘脑腹外侧视前区，A2A受体水平较低，腺苷在该区域的睡眠调节中起重要作用。尽管最初认为主要依赖A1受体，但在此我们综述了最近的研究，这些研究表明腺苷的促眠作用很大程度上由下丘脑A2A受体介导。因此，A2A受体拮抗剂可被视为发作性睡病和其他与睡眠相关疾病的一种可能治疗方法。最后，伤害感受是另一种先前认为主要涉及A1受体的由腺苷调节的神经功能。尽管关于激动剂和拮抗剂作用的文献存在一些相互矛盾之处，这可能部分归因于现有药物缺乏选择性，但对A2A受体基因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治疗潜力，特别是在高强度刺激普遍存在的情况下。
