Identification of the dopamine autoreceptor in the guinea‐pig retina as D 2 receptor using novel subtype‐selective antagonists

Dopamine release in the retina is subject to modulation via autoreceptors, which belong to the D 2 receptor family (encompassing the D 2 , D 3 and D 4 receptors). The aim of the present study was to determine the receptor sub type (D 2 vs D 3 ) involved in the inhibition of dopamine release in guinea‐pig retinal discs, using established (haloperidol, ( S )‐nafadotride) and novel dopamine receptor antagonists (ST‐148, ST‐198). hD 2L and hD 3 receptors were expressed in CHO cells and the p K i values determined in binding studies with [ 125 I]‐iodosulpride were: haloperidol 9.22 vs 8.54; ST‐148 7.85 vs 6.60; ( S )‐nafadotride 8.52 vs 9.51; ST‐198 6.14 vs 7.92. The electrically evoked tritium overflow from retinal discs preincubated with [ 3 H]‐noradrenaline (which represents quasi‐physiological dopamine release) was inhibited by the dopamine receptor agonists B‐HT 920 (talipexole) and quinpirole (maximally by 82 and 71%; pEC 50 5.80 and 5.83). The concentration‐response curves of these agonists were shifted to the right by haloperidol (apparent pA 2 8.69 and 8.23) and ST‐148 (7.52 and 7.66). ( S )‐Nafadotride 0.01 μ M and ST‐198 0.32 μ M did not affect the concentration‐response curve of B‐HT 920. The dopamine autoreceptor in the guinea‐pig retina can be classified as a D 2 receptor. ST‐148 and ST‐198 show an improved selectivity for D 2 and D 3 receptors when compared to haloperidol and ( S )‐nafadotride, respectively.British Journal of Pharmacology (2001) 133 , 1243–1248; doi: 10.1038/sj.bjp.0704192