DOPAMINERGIC & GABAERGIC ACTIONS OF PALLIDAL DISCHARGE

我们目前的目标是确定(1)多巴胺通过D1和D2受体对苍白球外节和内节神经元的紧张性和时相放电的作用，以及(2)纹状体GABA对纹状体输出神经元的影响。通过在三只猴子身上植入PAN-PVC管，药物已经应用于纹状体。总而言之，Dubach博士开发的技术使管子准确地沿着壳核外侧部分的弯曲纵向轨迹放置。伊顿博士使用高效液相色谱法显示，在体外，通过较薄的管壁，多巴胺的回收率几乎为100%。将GABAA拮抗剂荷包牡丹碱通过植入的管子直接注入壳核，可导致苍白球神经元出现局限性运动障碍和停顿-阵发性放电。在爆发之前，通常会有短暂的停顿，但并非总是如此。暂停/爆发发作不是在随机时间发生的，而是在不同方向运动期间的不同特定时间发生的。我们对数据的解读表明，被阻断的抑制可能是由与发送到纹状体输出神经元的信号相同或相关的运动信号以前馈方式驱动的。我们已经成功地应用了D_1选择性拮抗剂SCH23390和D_2选择性拮抗剂拉氯匹特来监测苍白球神经元的行为和记录。在高浓度的情况下，类似于其他人向大脑皮层注射的药物，这两种药物都会中断行为，在SCH23390的情况下，会导致嗜睡。我们已经以十倍的步幅将浓度降低了两次，发现行为中断的时间和恢复行为的洗脱时间都是剂量依赖的。我们目前正在分析同时记录的苍白球神经元的行为和活动，以确定随着药物效应的开始和结束，任务的不同方面和相关的苍白球放电是如何变化的。

Our current objectives are to determine (1) the actions of dopamine via D1 and D2 receptors on tonic and phasic discharge of neurons in external and internal pallidal segments, and (2) the effects of striatal GABA on striatal output neurons. Pharmacological agents have been applied to the striatum through implanted PAN-PVC tubing in three monkeys. In all, the technique developed by Dr. Dubach resulted in accurate placement of the tubing along a curved longitudinal trajectory in the lateral portion of the putamen. Dr. Eaton has used HPLC to show almost 100% recovery of dopamine across the thinner-walled tubing in vitro. Application of the GABAA antagonist bicuculline directly into the putamen through the implanted tubing resulted in localized dyskinesias and pause-burst episodes of discharge in pallidal neurons. The bursts were usually, but not always, preceded by brief pauses. The pause/burst episodes did not occur at random times, but at different particular times during movements in different directions. We interpret the data to indicate that the inhibition being blocked was driven, probably in a feed-forward manner, by motor signals that were the same as or related to signals sent to striatal output neurons. We have applied the D1-selective antagonist SCH23390 and the D2-selective antagonist raclopide successfully while monitoring behavior and recording from pallidal neurons. In high concentrations, similar to those injected by others into the cortex, both agents interrupted behavior and, in the case of SCH23390, caused drowsiness. We have reduced the concentration twice in tenfold steps and found that the time to behavioral interruption and the washout time to restore behavior are both dose-dependent. We currently are analyzing both the behavior and the activity of concurrently recorded pallidal neurons to determine how different aspects of the task and the related pallidal discharge changed as the drug effect began and ended.