Freeman K A, Tallarida R J
Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania.
J Pharmacol Exp Ther. 1994 Feb;268(2):629-38.
The control of dopamine release by negative feedback via dopaminergic autoreceptors has been well established. Using previously derived mathematical equations, we have incorporated this feedback component into a mass-action binding model in which the rate of ligand release is a function of the quantity that is bound. A consequence of this model is that competitive antagonists augment release, whereas competing agonists reduce such release. In order to obtain values of the parameters needed in the feedback equations, in vivo microdialysis was used to deliver drugs locally to the rat striatum and to monitor the resulting changes in extracellular dopamine levels. The dopamine agonists apomorphine and quinpirole and the antagonists haloperidol and sulpiride were individually infused into the rat striatum via the microdialysis probe, and the effect of each on extracellular dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic levels was recorded. The data obtained from the microdialysis experiments were used to construct dopamine's control curve, a new quantitative concept that describes the feedback control of the dopaminergic system. Once known, the ligand's control curve has predictive value that may be useful in the design of efficient drug tests. Alterations of dopamine's control curve, which may occur with aging, drug addiction and pathological states, can now be studied and may provide new insights for potential therapeutic strategies.
多巴胺能自身受体通过负反馈对多巴胺释放的控制已得到充分证实。利用先前推导的数学方程，我们将这种反馈成分纳入了一个质量作用结合模型，其中配体释放速率是结合量的函数。该模型的一个结果是，竞争性拮抗剂会增加释放，而竞争性激动剂则会减少这种释放。为了获得反馈方程所需的参数值，采用体内微透析将药物局部递送至大鼠纹状体，并监测由此导致的细胞外多巴胺水平变化。通过微透析探针将多巴胺激动剂阿扑吗啡和喹吡罗以及拮抗剂氟哌啶醇和舒必利分别注入大鼠纹状体，并记录每种药物对细胞外多巴胺、3,4-二羟基苯乙酸和高香草酸水平的影响。从微透析实验中获得的数据用于构建多巴胺的控制曲线，这是一个描述多巴胺能系统反馈控制的新的定量概念。一旦确定，配体的控制曲线具有预测价值，可能有助于高效药物测试的设计。现在可以研究多巴胺控制曲线的改变，这种改变可能随着衰老、药物成瘾和病理状态而发生，并可能为潜在的治疗策略提供新的见解。
