Lau Y S, Runice C, Dowd F
J Pharmacol Exp Ther. 1984 Apr;229(1):32-7.
In the present study we investigated several pharmacological and biochemical parameters in striatal preparations of rats which were treated chronically with a selective D2 receptor antagonist, sulpiride. Chronic sulpiride treatment in rats (50 mg/kg s.c. for 20 days) potentiated stereotyped responses by apomorphine (0.1-2.5 mg/kg). In association with the dopaminergic behavior supersensitivity, we observed a significant increase in the number of specific [3H]spiperone binding sites (D2 receptors) in the striatum without affecting the ligand binding affinity constant. We further observed a marked increase in the sensitivity of the protein kinase to calcium (0.1-0.5 mM) and calmodulin (1 micrograms) in these rats. The D1 receptor functions which are represented by the basal and dopamine-stimulated adenylate cyclase and the cyclic AMP-dependent protein kinase activity were not changed after chronic sulpiride treatment. In vitro, pretreatment of striatal particulates with the Ca++-chelating agent ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid (1.2 mM) to remove endogenous Ca++ and calmodulin or the addition of Ca++ and calmodulin to the striatal particulates did not affect the binding affinities of dopamine agonists and antagonists to the receptors. Therefore, the increased sensitivity of the calmodulin-dependent system seen in chronic sulpiride-treated rats correlates with the increased number of D2 receptors in striatal dopamine receptor supersensitivity.
在本研究中，我们调查了长期用选择性D2受体拮抗剂舒必利治疗的大鼠纹状体制剂中的几个药理学和生化参数。大鼠长期接受舒必利治疗（皮下注射50mg/kg，持续20天）增强了阿扑吗啡（0.1 - 2.5mg/kg）引起的刻板反应。与多巴胺能行为超敏反应相关，我们观察到纹状体中特异性[3H]螺哌隆结合位点（D2受体）的数量显著增加，而不影响配体结合亲和力常数。我们还进一步观察到这些大鼠中蛋白激酶对钙（0.1 - 0.5mM）和钙调蛋白（1微克）的敏感性显著增加。以基础和多巴胺刺激的腺苷酸环化酶以及环磷酸腺苷依赖性蛋白激酶活性为代表的D1受体功能在长期舒必利治疗后未发生变化。在体外，用Ca++螯合剂乙二醇双（β - 氨基乙醚）-N，N'-四乙酸（1.2mM）预处理纹状体微粒以去除内源性Ca++和钙调蛋白，或者向纹状体微粒中添加Ca++和钙调蛋白，均不影响多巴胺激动剂和拮抗剂与受体的结合亲和力。因此，在长期接受舒必利治疗的大鼠中观察到的钙调蛋白依赖性系统敏感性增加与纹状体多巴胺受体超敏反应中D2受体数量增加相关。
