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.
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