Zhang S P, Zhou L W, Natsukari N, Weiss B
Department of Pharmacology, Medical College of Pennsylvania/EPPI, Philadelphia 19129.
Neurochem Int. 1993 Oct;23(4):361-72. doi: 10.1016/0197-0186(93)90080-o.
Continuously administering the D2 dopamine agonist quinpirole to mice for 6 days produces an initial stereotypy that is reduced by 2 h and is absent from 3 h to the 6 day duration of the infusion. In an attempt to determine the biochemical correlates for this down-regulation of stereotypic behavior, the effects of continuously administering quinpirole on a number of biochemical parameters were measured in mouse corpus striatum. After 6 days of infusion with quinpirole, the striata were analyzed for D1 and D2 dopamine receptors, for the activities of several protein phosphorylation reactions which are thought to be involved in receptor activity and for the levels of calmodulin-binding proteins. Quinpirole decreased the D2 receptors in striatum and produced a small but statistically non-significant increase in D1 receptors, resulting in a significant increase in the ratio of D1 to D2 dopamine receptors. An examination of the effects of quinpirole on protein phosphorylation systems showed that the agonist failed to alter the activity of cyclic AMP-dependent protein kinase or protein kinase C but significantly decreased the Ca2+/calmodulin-dependent phosphorylation of striatal membranes. However, this decrease in Ca2+/calmodulin-dependent phosphorylation was not associated with changes in the levels of calmodulin-binding proteins. The results suggest that behavioral down-regulation following the continuous administration of a D2 dopamine agonist is associated with at least two biochemical events: a down-regulation of D2 dopamine receptors and a decrease of Ca2+/calmodulin-dependent phosphorylation of striatal membranes.
连续6天给小鼠注射D2多巴胺激动剂喹吡罗，会产生一种初始刻板行为，这种行为在2小时后会减弱，在注射3小时后至6天期间则消失。为了确定这种刻板行为下调的生化相关因素，在小鼠纹状体中测量了连续注射喹吡罗对一些生化参数的影响。在用喹吡罗注射6天后，分析纹状体中的D1和D2多巴胺受体、几种被认为与受体活性有关的蛋白质磷酸化反应的活性以及钙调蛋白结合蛋白的水平。喹吡罗降低了纹状体中的D2受体，并使D1受体有小幅但在统计学上无显著意义的增加，导致D1与D2多巴胺受体的比率显著增加。对喹吡罗对蛋白质磷酸化系统影响的研究表明，该激动剂未能改变环磷酸腺苷依赖性蛋白激酶或蛋白激酶C的活性，但显著降低了纹状体膜的Ca2+/钙调蛋白依赖性磷酸化。然而，Ca2+/钙调蛋白依赖性磷酸化的这种降低与钙调蛋白结合蛋白水平的变化无关。结果表明，连续给予D2多巴胺激动剂后行为下调至少与两个生化事件有关：D2多巴胺受体的下调和纹状体膜Ca2+/钙调蛋白依赖性磷酸化的降低。
