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

1 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 su btype (D-2 vs D-3) involved in the inhibition of dopamine release in guinea pig retinal discs. using established (haloperidol, (S)-nafadotride) and nov el dopamine receptor antagonists (ST-148, ST-198). 2 hD(2L) and hD(3) receptors were expressed in CHO cells and the pK(i) valu es determined in binding studies with [I-125]-iodosulpride were: haloperido l 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. 3 The electrically evoked tritium overflow from retinal discs preincubated with [H-3]-noradrenaline (which represents quasi-physiological dopamine rel ease) 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 conce ntration-response curves of these agonists were shifted to the right by hal operidol (apparent pA(2) 8.69 and 8.23) and ST-148 (7.52 and 7.66). (S)-Naf adotride 0.01 muM and ST-198 0.32 muM did not affect the concentration-resp onse curve of B-HT 920 4 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 .