Keefe K A, Gerfen C R
Section of Neuroanatomy, National Institute of Mental Health, Bethesda, MD 20892, USA.
Neuroscience. 1995 Jun;66(4):903-13. doi: 10.1016/0306-4522(95)00024-d.
Manipulations of D1- or D2-dopamine receptors have differential and selective effects on the striatonigral and striatopallidal output pathways of the striatum, respectively. However, combined stimulation of these receptors produces synergistic responses. To examine the locus of this interaction in vivo, we infused D1- or D2-receptor agents into the striatum of freely moving, dopamine-depleted rats given systemic injections of the D1 agonist SKF 38393 and the D2 agonist quinpirole. Expression of the immediate early genes zif268 and c-fos, as determined by in situ hybridization histochemistry, was used as a measure of changes in the function of striatal neurons. Systemic administration of SKF 38393 produced a dose-dependent increase in the expression of immediate early genes in the dopamine-depleted striatum. Quinpirole, on the other hand, decreased the basal expression of zif268 in both the lesioned and intact striatum. However, combined administration of quinpirole with SKF 38393 significantly enhanced immediate early gene expression in the dopamine-depleted striatum relative to that seen with SKF 38393 alone. Intrastriatal infusion of SKF 38393 produced a concentration-dependent increase in immediate early gene expression in the striatum. Furthermore, intrastriatal application of the D1-receptor antagonist SCH 23390 blocked the induction of immediate early genes by SKF 38393 given systemically either alone or with quinpirole. The induction of immediate early genes by co-administration of SKF 38393 and quinpirole was also significantly attenuated by intrastriatal administration of the D2-receptor antagonist eticlopride. These data show that D1-D2 synergy is operative in the dopamine-depleted striatum, is reflected in increases in the expression of the immediate early genes zif268 and c-fos, and is a consequence of activation of both D1 and D2 receptors within the striatum rather than in extrastriatal sites. The data further suggest that the enhanced induction of immediate early genes in the dopamine-depleted striatum of rats receiving SKF 38393 with quinpirole reflects a D2-mediated potentiation of a D1-dependent process.
对D1或D2多巴胺受体的调控分别对纹状体的黑质纹状体和纹状体苍白球输出通路具有不同的选择性作用。然而，联合刺激这些受体会产生协同反应。为了在体内研究这种相互作用的位点，我们将D1或D2受体药物注入自由活动、多巴胺耗竭的大鼠纹状体中，这些大鼠全身注射了D1激动剂SKF 38393和D2激动剂喹吡罗。通过原位杂交组织化学测定即刻早期基因zif268和c-fos的表达，以此作为纹状体神经元功能变化的指标。全身给予SKF 38393会使多巴胺耗竭的纹状体中即刻早期基因的表达呈剂量依赖性增加。另一方面，喹吡罗降低了损伤和完整纹状体中zif268的基础表达。然而，与单独给予SKF 38393相比，喹吡罗与SKF 38393联合给药显著增强了多巴胺耗竭的纹状体中即刻早期基因的表达。纹状体内注入SKF 38393会使纹状体中即刻早期基因的表达呈浓度依赖性增加。此外，纹状体内应用D1受体拮抗剂SCH 23390可阻断单独或与喹吡罗联合全身给予SKF 38393时对即刻早期基因的诱导。纹状体内给予D2受体拮抗剂依替必利也可显著减弱SKF 38393和喹吡罗联合给药对即刻早期基因的诱导。这些数据表明，D1-D2协同作用在多巴胺耗竭的纹状体中起作用，表现为即刻早期基因zif268和c-fos表达增加，并且是纹状体内D1和D2受体激活的结果，而非纹状体以外部位。数据进一步表明，在接受SKF 38393和喹吡罗的大鼠多巴胺耗竭纹状体中，即刻早期基因诱导增强反映了D2介导的对D1依赖性过程的增强作用。
