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BEHAVIORAL PHARMACOLOGY

Effects of Dopamine D₁ Ligands on Eye Blinking in Monkeys: Efficacy, Antagonism, and D₁/D₂ Interactions

Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (E.M.J.); and Department of Psychiatry, Harvard Medical School/McLean Hospital, Belmont, Massachusetts (J.B.)

Dopamine D₁ ligands have been classified and ordered according to efficacy in both in vitro and in vivo studies. In the present experiments, dopamine D₁ 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 D₂ receptor agonists and indirect dopamine agonists. The results show that D₁ agonists increased eye blinking in an efficacy-related manner, whereas the D₁ receptor blocker SCH 39166 [(–)-trans-6,7,7,8,9,13-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo[d]naphtho[2,1-b]azepine] only decreased rates of eye blinking. D₁ high-efficacy agonists induced rates of eye blinking that were 2- to 3-fold greater than observed with dopamine D₂ agonists and indirect agonists. In drug combination experiments, increases in eye blinking induced by the D₁ 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 D₁ 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 D₁ receptor mediation of these behavioral effects. The dopamine D₂ agonist (+)-PHNO [(+)-N-propyl-hydroxynaphthoxazine], which selectively activates dopamine D₂ receptors, also attenuated D₁ agonist-induced increase in eye blinking, suggesting that D₂ receptor actions may inhibit D₁-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 D₁ signaling and as a functional assay of agonist efficacy at dopamine D₁ receptors.

Address correspondence to: Dr. Jack Bergman, McLean Hospital, 115 Mill Street, Belmont MA 02478. E-mail: jbergman{at}hms.harvard.edu