Pharmacological characterization of the effects of dopamine D(1) agonists on eye blinking in rats

Dopamine D(1)-like partial agonists antagonize some abuse-related effects of cocaine and have been proposed as candidate medications for psychostimulant abuse. Earlier studies have showed that D(1)-like agonists increase eye blinking in monkeys and that the magnitude of this effect may be related to agonist efficacy. These studies characterized the effects of D(1)-like agonists on eye blinking in female Sprague-Dawley rats placed in customized restraint tubes. After vehicle injections, eye blink rates averaged 2.1+/-0.25 blinks/min, or 31+/-4 blinks/15 min. The D(1)-like agonists SKF 82958 and R(+)-6Br-APB dose-dependently increased eye blinking to 136 and 124/15 min, respectively. The selective D(1)-like antagonist SCH 23390 decreased eye blinking and the peripherally selective D(1)-like agonist fenoldopam, the D(2)-like agonist (+)PHNO, and the indirect dopamine agonist methamphetamine all failed to alter eye blink rates relative to vehicle levels. Additional studies with unique congeners and isomers of the D(1)-like partial agonist SKF 83959, MCL 202, MCL 204, MCL 206, MCL 207 and MCL 209, resulted in only moderate increases in eye blink rates (27-84 blinks/15 min). These effects were dose-related for one compound, MCL 209 (max 84+/-19 blinks/15 min) and plateaued at the highest doses, suggestive of partial agonist effects. Additionally, the agonist MCL 206, like the D(1)antagonist SCH 23390, antagonized the effects of SKF 82958 on eye blinking. The findings suggest that D(1)-like agonists increase eye blinking in rats and that these effects may provide a simple measure that can be used to distinguish partial D(1)-like ligands. Further studies with novel D(1)-like partial agonists may be useful in the development of pharmacotherapies for cocaine abuse.