PHARMACOLOGICAL DIFFERENCES BETWEEN THE D-2 AUTORECEPTOR AND THE D-1 DOPAMINE RECEPTOR IN RABBIT RETINA

Abstract

The effect of dopamine receptor agonists and antagonists was studied on the Ca-dependent release of [3H]dopamine elicited by field stimulation at 3 Hz for a duration of 1 min (20 mA, 2 msec) from the rabbit retina in vitro and on adenylate cyclase activity in homogenates of rabbit retina. The relative order of potency of dopamine receptor agonists to inhibit the stimulation-evoked [3H]dopamine release was pergolide > bromocriptine > apomorphine > LY 141865 > N,N-di-n-propyldopamine .gtoreq. dopamine. The relative order of potencies of dopamine receptor antagonists to increase [3H]dopamine release was: S-sulpiride .gtoreq. domperidone .gtoreq. spiroperidol > metoclopramide > fluphenazine .gtoreq. R-sulpiride. .alpha.-Flupenthixol (0.01-1 .mu.M) and (+)-butaclamol (0.01-1 .mu.M) did not increase [3H]dopamine overflow when added alone, but they antagonized the concentration-dependent inhibitory effect of apomorphine (0.1-10 .mu.M). The dopamine inhibitory autoreceptor involved in the modulation of dopamine release from the rabbit retina possesses the pharmacological characteristics of a D-2 dopamine receptor. Maximal stimulation by 30 .mu.M dopamine resulted in a 3-fold increase in adenylate cyclase activity with half-maximal stimulation occurring at a concentration of 2.46 .mu.M. Apomorphine and pergolide elicited a partial stimulation of adenylate cyclase activity. At low concentrations both compounds were more potent than dopamine. N,N-di-n-propyldopamine was 30 times less potent than dopamine, and bromocriptine was unable to stimulate adenylate cyclase activity. The relative order of potencies of dopamine antagonists to inhibit the dopamine-stimulated adenylate cyclase was .alpha.-flupenthixol .gtoreq. fluphenazine .gtoreq. (+)butaclamol > spiperone. Domperidone, metoclopramide, the isomers of sulpiride, .beta.-flupenthixol and (-)-butaclamol were inactive in concentrations up to 100 .mu.M. The receptor linked to the dopamine-stimulated adenylate cyclase of the rabbit retina possesses the characteristics of the D-1 receptor. The dopamine receptor mediating inhibition of dopamine release and the dopamine receptor linked to the stimulation of adenylate cyclase in rabbit retina are pharmacologically distinct, as they possess different affinities for both dopamine agonists and antagonists.