Fuxe Kjell, Ferré Sergi, Genedani Susanna, Franco Rafael, Agnati Luigi F
Karolinska Institutet, Department of Neuroscience, Retzius väg 8, S-171 77 Stockholm, Sweden.
Physiol Behav. 2007 Sep 10;92(1-2):210-7. doi: 10.1016/j.physbeh.2007.05.034. Epub 2007 May 21.
The dopamine D1 and D2 receptors are major receptors in the regulation of striatal function and striatal adenosine A1 and A2A receptors are major modulators of their signaling. The evidence suggests the existence of antagonistic A1-D1 heteromeric receptor complexes in the basal ganglia and prefrontal cortex and especially in the direct striatonigral-striatoentopeduncular GABA pathways. The neurochemical and behavioral findings showing antagonistic A1-D1 receptor interactions can be explained by the existence of such A1-D1 heteromeric receptor complexes and of antagonistic interactions at the level of the second messengers. In contrast, A2A-D2 receptor heteromers may exist in the dorsal and ventral striato-pallidal GABA pathways, where activation of A2A receptors reduces D2 receptor recognition, coupling and signaling. As a result of the A2A receptor-induced reduction of D2 receptor signaling, the activity of these GABA neurons is increased resulting in reduced motor and reward functions mediated via the indirect pathway, causing a reduced glutamate drive to the prefrontal and motor areas of the cerebral cortex. Thus, A2A receptor antagonists and A2A receptor agonists, respectively, may offer novel treatments of Parkinson's disease (reduced D2 receptor signaling) and of schizophrenia and drug addiction (increased D2 receptor signaling).
多巴胺D1和D2受体是调节纹状体功能的主要受体，纹状体腺苷A1和A2A受体是其信号传导的主要调节因子。有证据表明，在基底神经节和前额叶皮质，尤其是在直接的纹状体黑质-纹状体脚内核GABA通路中，存在拮抗型A1-D1异聚体受体复合物。显示A1-D1受体相互作用拮抗的神经化学和行为学研究结果，可以通过这种A1-D1异聚体受体复合物的存在以及第二信使水平的拮抗相互作用来解释。相比之下，A2A-D2受体异聚体可能存在于背侧和腹侧纹状体苍白球GABA通路中，其中A2A受体的激活会降低D2受体的识别、偶联和信号传导。由于A2A受体诱导的D2受体信号传导减少，这些GABA神经元的活性增加，导致通过间接通路介导的运动和奖赏功能降低，从而减少了对大脑皮质前额叶和运动区域的谷氨酸驱动。因此，A2A受体拮抗剂和A2A受体激动剂可能分别为帕金森病（D2受体信号传导减少）以及精神分裂症和药物成瘾（D2受体信号传导增加）提供新的治疗方法。
