Effects of dopamine D1 ligands on eye blinking in monkeys: Efficacy, antagonism, and D1/D2 interactions

Dopamine D-1 ligands have been classified and ordered according to efficacy in both in vitro and in vivo studies. In the present experiments, dopamine D-1 ligands reported to differ in in vitro efficacy were evaluated for efficacy-related effects on eye blinking in squirrel monkeys. Additional comparisons were made with the effects of D-2 receptor agonists and indirect dopamine agonists. The results show that D-1 agonists increased eye blinking in an efficacy-related manner, whereas the D-1 receptor blocker SCH 39166 [(-)-trans-6,7,7alpha, 8,9,13beta-hexahydro- 3-chloro-2-hydroxy-N-methyl-5H-benzo[d] naphtho[ 2,1-b] azepine] only decreased rates of eye blinking. D-1 high-efficacy agonists induced rates of eye blinking that were 2- to 3-fold greater than observed with dopamine D-2 agonists and indirect agonists. In drug combination experiments, increases in eye blinking induced by the D-1 high-efficacy agonist R-(+)-6-Br-APB [R-(+)-6-bromo-7,8-dihydroxy-3-allyl-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide] were antagonized by both the D-1 antagonist SCH 39166 and the lower efficacy agonist SKF 83959 [6-chloro-7,8-dihydroxy-3- methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide], consistent with dopamine D 1 receptor mediation of these behavioral effects. The dopamine D-2 agonist (+)-PHNO [(+)-N-propyl-hydroxynaphthoxazine], which selectively activates dopamine D-2 receptors, also attenuated D-1 agonist-induced increase in eye blinking, suggesting that D-2 receptor actions may inhibit D-1-mediated increases in eye blinking. Overall, eye blink rate appears to be a robust behavioral measure that can be used to measure changes in dopaminergic D-1 signaling and as a functional assay of agonist efficacy at dopamine D-1 receptors.