Rubinstein M, Muschietti J P, Gershanik O, Flawia M M, Stefano F J
Instituto de Investigaciones Farmacológicas (CONICET), Facultad de Medicina (UBA), Argentina.
J Pharmacol Exp Ther. 1990 Feb;252(2):810-6.
Mice receiving reserpine (1 mg/kg/day) during 5 days develop behavioral supersensitivity. To study the possible molecular correlates of these adaptive changes we compared binding parameters of D1 and D2 receptors and adenylate cyclase activity in striata from normal and reserpinized mice. Saturation curves using [3H]SCH 23390 showed no changes in maximum binding capacity (Bmax) or Kd of striatal D1 receptors taken from control or 5 days reserpine-treated mice. However, [3H]spiperone saturation curves showed a 31% increase in D2 receptors Bmax with no changes in Kd. Dopamine competition of [3H]SCH 23390 and [3H]spiperone binding in mouse striatum was also performed. Analysis of data by LIGAND showed that dopamine recognizes two subpopulations for D1 and for D2 receptors. The proportion of receptors in the high affinity state (D1high and D2high) were increased in reserpine-treated animals. The addition of 100 microM GTP produced a complete conversion of D1high and D2high receptors into their low-affinity states in striata from control and reserpinized mice. Five days of reserpine treatment increased basal adenylate cyclase activity of mouse striatum in the presence of Mn++ or Mg++ ions. Concentration curves with dopamine, NaF or forskolin revealed shifts to the left and higher maximum responses without changes in EC50 values in striata from reserpinized mice. Thus, a prolonged reserpine treatment produces marked changes in D1 and D2 receptors increasing the proportion of high affinity state subpopulations and the total Bmax of D2 receptors. Also, dopamine function may be enhanced through an increment of the catalytic component of striatal adenylate cyclase.
连续5天接受利血平（1毫克/千克/天）治疗的小鼠会出现行为超敏反应。为了研究这些适应性变化可能的分子关联，我们比较了正常小鼠和经利血平处理的小鼠纹状体中D1和D2受体的结合参数以及腺苷酸环化酶活性。使用[3H]SCH 23390绘制的饱和曲线显示，取自对照小鼠或经5天利血平处理的小鼠纹状体D1受体的最大结合容量（Bmax）或解离常数（Kd）没有变化。然而，[3H]螺哌隆饱和曲线显示D2受体的Bmax增加了31%，而Kd没有变化。还进行了[3H]SCH 23390和[3H]螺哌隆在小鼠纹状体中的多巴胺竞争实验。用LIGAND软件分析数据表明，多巴胺可识别D1和D2受体的两个亚群。在经利血平处理的动物中，高亲和力状态（D1high和D2high）的受体比例增加。在对照小鼠和经利血平处理的小鼠纹状体中，添加100微摩尔GTP可使D1high和D2high受体完全转变为低亲和力状态。利血平处理5天可增加在存在锰离子或镁离子时小鼠纹状体的基础腺苷酸环化酶活性。用多巴胺、氟化钠或福司可林绘制的浓度曲线显示，来自经利血平处理的小鼠纹状体的曲线向左移动且最大反应更高，而半数有效浓度（EC50）值没有变化。因此，长期利血平治疗会使D1和D2受体发生显著变化，增加高亲和力状态亚群的比例以及D2受体的总Bmax。此外，多巴胺功能可能通过纹状体腺苷酸环化酶催化成分的增加而增强。
