Ferre S, von Euler G, Johansson B, Fredholm B B, Fuxe K
Department of Histology and Neurobiology, Karolinska Institutet, Stockholm, Sweden.
Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7238-41. doi: 10.1073/pnas.88.16.7238.
Since high-affinity adenosine A2 receptors (A2a) are localized exclusively in dopamine-rich regions in the central nervous system and mediate inhibition of locomotor activity, we have examined the effect of A2a receptor activation on D1 and D2 receptor binding in membrane preparations of the rat striatum. The A2a agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'- N-ethylcarboxamidoadenosine (CGS 21680) increased the Kd of the dopamine D2 agonist L-(-)-N-[3H]propylnorapomorphine without affecting the Bmax. The increase in Kd was maximal (40%) at 30 nM CGS 21680. CGS 21680 (30 nM) decreased the dopamine-induced inhibition of [3H]raclopride (a D2 antagonist) binding due to an increase (about 3-fold) in KH and KL, the dissociation constants of high- and low-affinity binding sites. The effects of CGS 21680 were antagonized by the adenosine antagonist 8-phenyltheophylline (10 microM). (-)-N6-(2-Phenylisopropyl)adenosine produced an effect similar to that of CGS 21680, provided the concentration used was high enough to stimulate A2a receptors (300 nM). GTP (50 microM) also decreased the dopamine-induced inhibition of [3H]raclopride binding but, in contrast to CGS 21680, GTP decreased the proportion of D2 receptors in the high-affinity state. CGS 21680 (30 nM) did not affect the Kd or Bmax of [3H]raclopride and failed to affect ligand binding to D1 receptors. Thus, stimulation of A2a receptors potently reduces the affinity of D2 agonist binding sites within the plasma membrane of striatal neurons. This A2a-D2 interaction may underlie the neuroleptic-like actions of adenosine agonists and the enhancing effects of adenosine antagonists, such as caffeine, on locomotor activity.
由于高亲和力的腺苷A2受体（A2a）仅定位于中枢神经系统中富含多巴胺的区域并介导运动活性的抑制，我们研究了A2a受体激活对大鼠纹状体膜制剂中D1和D2受体结合的影响。A2a激动剂2-[对-(2-羧乙基)苯乙氨基]-5'-N-乙基羧酰胺基腺苷（CGS 21680）增加了多巴胺D2激动剂L-(-)-N-[3H]丙基去甲阿朴吗啡的解离常数（Kd），而不影响最大结合容量（Bmax）。在30 nM CGS 21680时，Kd的增加最大（40%）。CGS 21680（30 nM）减少了多巴胺诱导的[3H]雷氯必利（一种D2拮抗剂）结合的抑制，这是由于高亲和力和低亲和力结合位点的解离常数KH和KL增加（约3倍）。CGS 21680的作用被腺苷拮抗剂8-苯基茶碱（10 microM）拮抗。(-)-N6-(2-苯异丙基)腺苷产生了与CGS 21680类似的作用，前提是所用浓度足够高以刺激A2a受体（300 nM）。鸟苷三磷酸（GTP，50 microM）也减少了多巴胺诱导的[3H]雷氯必利结合的抑制，但与CGS 21680相反，GTP降低了高亲和力状态下D2受体的比例。CGS 21680（30 nM）不影响[3H]雷氯必利的Kd或Bmax，并且未能影响配体与D1受体的结合。因此，刺激A2a受体可有效降低纹状体神经元质膜内D2激动剂结合位点的亲和力。这种A2a-D2相互作用可能是腺苷激动剂的抗精神病样作用以及腺苷拮抗剂（如咖啡因）对运动活性的增强作用的基础。
