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. 2001 Aug;133(8):1243–1248. doi: 10.1038/sj.bjp.0704192

Identification of the dopamine autoreceptor in the guinea-pig retina as D2 receptor using novel subtype-selective antagonists

Bernd Weber 1, Eberhard Schlicker 1,*, Pierre Sokoloff 2, Holger Stark 3
PMCID: PMC1621144  PMID: 11498509

Abstract

  1. Dopamine release in the retina is subject to modulation via autoreceptors, which belong to the D2 receptor family (encompassing the D2, D3 and D4 receptors). The aim of the present study was to determine the receptor subtype (D2 vs D3) 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).

  2. hD2L and hD3 receptors were expressed in CHO cells and the pKi values determined in binding studies with [125I]-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.

  3. The electrically evoked tritium overflow from retinal discs preincubated with [3H]-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%; pEC50 5.80 and 5.83). The concentration-response curves of these agonists were shifted to the right by haloperidol (apparent pA2 8.69 and 8.23) and ST-148 (7.52 and 7.66). (S)-Nafadotride 0.01 μM and ST-198 0.32 μM did not affect the concentration-response curve of B-HT 920.

  4. The dopamine autoreceptor in the guinea-pig retina can be classified as a D2 receptor. ST-148 and ST-198 show an improved selectivity for D2 and D3 receptors when compared to haloperidol and (S)-nafadotride, respectively.

Keywords: Guinea-pig retina, Dopamine D2/D3 receptor, Haloperidol, (S)-Nafadotride, ST-148, ST-198, quinpirole, B-HT 920, dopamine release, autoreceptor

Introduction

Dopamine is located in the amacrine and interplexiform cells of the inner nuclear layer of the retina (Smeets & Gonzalez, 2000). In the guinea-pig retina dopamine has recently been shown to be localized to amacrine cells type 1 and 2 (Oh et al., 1999). Some inherent functions of the retina involve the release of dopamine, e.g., dark-light adaptation (Djamgoz & Wagner, 1992) or motion detection (Mora-Ferrer & Gangluff, 2000).

Retinal dopamine release is subject to modulation via inhibitory autoreceptors, which have been identified in the retina of teleosts (Rashid et al., 1993), rabbits (Dubocovich & Weiner, 1985) and guinea-pigs (Weber et al., 2001), and belong to the dopamine D2-subfamily (which encompasses the D2, D3 and D4 receptors; for review, see Strange, 2001). For some dopamine autoreceptors located outside the retina, e.g., in the brain, the dopamine receptor subtype within the dopamine D2-subfamily has been determined. The autoreceptor in the human neocortex and in the rat striatum can be subclassified as D2 (Fedele et al., 1999) whereas the autoreceptor on the tuberoinfundibular neurones of the rat is D3 (Lin et al., 2000). It may be of particular interest to determine the exact receptor subtype also for the dopamine autoreceptor in the retina since dopamine in the retina is highly relevant with respect to experimental models of myopia (e.g., deprivation myopia in chickens is aggravated by the D2/D3 receptor antagonist sulpiride; Schaeffel et al., 1995).

In a study on guinea-pig retinal discs carried out for this purpose, we used haloperidol and (S)-nafadotride, which have a preference for the D2- or D3-receptor subtypes, respectively, and two novel substances ST-148 and ST-198, with a higher degree of selectivity for the D2- and D3-receptor subtypes, respectively (for chemical structures, see Figure 1). The agonists used in the present study, quinpirole and B-HT 920, possess a preference for the D3 over the D2 receptor (Levant, 1997; Wood et al., 2000). All experiments were performed on retinal discs preincubated with [3H]-noradrenaline, which in areas devoid of noradrenergic neurones like the retina of the guinea-pig is taken up (and released from) dopaminergic cells and offers advantages over the use of [3H]-dopamine itself (Schlicker et al., 1996).

Figure 1.

Figure 1

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Chemical structures of the novel dopamine D2 (ST-148) and D3 (ST-198) receptor antagonists.

Methods

Superfusion experiments

Male Dunkin-Hartley guinea-pigs were decapitated and the eyes were removed from the skull. The retina was carefully detached from other layers of the eye using a spatula and discs (diameter 3 mm) were punched out. For the experiments, a physiological salt solution (PSS) of the following composition was used (mM): NaCl 118, KCl 4.8, CaCl2 1.3, KH2PO4 1.2, MgSO4 1.2, NaHCO3 25, ascorbic acid 0.06, disodium EDTA 0.03, glucose 10; the solution was aerated with 95% O2 and 5% CO2 (pH 7.4).

Retinal discs preincubated with [3H]-noradrenaline 25 nM (specific activity 51.8–57.3 Ci mmol−1) (60 min; 37°C) were superfused with PSS (37°C) for 110 min. Tritium overflow was evoked by two 2-min periods of stimulation (3 Hz, 200 mA, 2 ms) after 40 and 90 min (S1, S2). In all experiments the PSS contained nomifensine 10 μM throughout superfusion. The antagonists under study were present in the PSS throughout superfusion, whereas the agonists were added to the PSS from 62 min of superfusion onward.

Binding studies

Membranes of CHO cell lines stably transfected with human dopamine D2L or D3 receptor DNA were taken for binding assays using [125I]-iodosulpride according to Sautel et al. (1995). Nonspecific binding was determined in the presence of emonapride 1 μM. Ki values were derived from IC50 values according to the Cheng-Prussoff equation (Cheng & Prussoff, 1973), taking into account the Kd of [125I]-iodosulpride for the respective receptors. Data were obtained from at least three separate experiments.

Calculations and statistics

Tritium overflow was calculated as the fraction of the tritium content of the slices at the beginning of the respective collection period (fractional rate of tritium efflux). Basal tritium efflux was quantified by calculating the ratio of the fractional rate in the 5-min period immediately before S2 (i.e. from 85–90 min; t2) over that in the collection period from 55–60 min (t1, i.e. in the 5-min sample collected just before the addition of the agonist to the superfusion medium). Stimulation-evoked tritium overflow was calculated by subtraction of the basal from the total tritium efflux during stimulation and the subsequent 13 min and was expressed as per cent of tritium present in the slice at the onset of stimulation (basal tritium efflux was assumed to decline linearly from the 5-min collection period before that to 15–20 min after onset of stimulation). To quantify the effects of agonists on the stimulated tritium overflow, the ratio of the overflow evoked by S2 over that evoked by S1 was determined. To determine the effects of antagonists on the evoked overflow, the S1 values obtained in the presence and absence of the respective antagonist were compared. To quantify agonist potencies, pEC50 values (negative logarithms of the concentration causing the half-maximal effect) were determined. Apparent pA2 values for antagonists were calculated according to formula 4 of Furchgott (1972).

Results are given as means±s.e.mean of n experiments. For comparison of mean values, Student's t-test was used; the Bonferroni correction was used, when two or more values were compared to the same control.

Drugs

(−)-[Ring-2,5,6-3H]noradrenaline (NEN, Zaventem, Belgium); [125I]-iodosulpride (Amersham Int., Buckinghamshire, U.K.); tetrodotoxin (Roth, Karlsruhe, Germany); haloperidol, quinpirole hydrochloride (RBI/Sigma, Munich, Germany); B-HT 920 (talipexole; 6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-amine dihydrochloride; Thomae, Biberach an der Riss, Germany); nomifensine (Hoechst, Frankfurt); emonapride (Yamanouchi, Tokyo, Japan); ST-148 (N-(4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl)-5-(dimethylamino)-naphthalene-1-sulphonamide) maleate and ST-198 (N-(4-[1,2,3,4-tetrahydroisoquinolin-2-yl]-butyl)-3-phenylacrylamide) maleate were synthesized by H. Stark; (S)-nafadotride (synthesized at the Unité de Neurobiologie et Pharmacologie Moléculaire, Centre Paul Broca). Stock solutions of the drugs were prepared with water, citrate buffer (0.1 mM, pH 4.8; tetrodotoxin), lactic acid (2 M; emonapride), HCl 0.01 M (haloperidol) or DMSO (ST-148, ST-198) and diluted to the concentration required. The solvents did not affect basal and evoked tritium overflow by themselves.

Results

Superfusion experiments

Basal tritium efflux was expressed as t1 or t2/t1. The t1 value was not affected by any of the antagonists under study (Table 1). The t2/t1 value was 0.58±0.08 in 43 control experiments in which no agonist or antagonist was present; similar t2/t1 values were obtained in experiments in which no agonist but one of the four antagonists was present (results not shown). B-HT 920 0.1–320 μM, quinpirole 0.1–100 μM, tetrodotoxin 1 μM and omission of Ca2+ ions did not alter t2/t1 values (results not shown).

Table 1.

Influence of the antagonists on basal and electrically evoked tritium outflow in guinea-pig retinal discs preincubated with [3H]-noradrenaline

graphic file with name 133-0704192t1.jpg

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The electrically evoked tritium overflow was expressed as S1 or S2/S1. To quantify the effects of antagonists (present in the medium during S1 and S2), S1 values were used. To quantify the effects of agonists (present in the medium during S2), S2/S1 values were considered. S1 values are shown in Table 1. S2/S1 values in agonist-free controls are given in the legends to Figures 2 and 3.

Figure 2.

Figure 2

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Effect of B-HT 920 on the electrically evoked tritium overflow from [3H]-noradrenaline-preincubated retinal discs and interaction with dopamine receptor antagonists. (A) shows the two classical dopamine receptor antagonists, in (B) the novel antagonists are depicted. The antagonists were present throughout the superfusion (110 min), B-HT 920 from 62 min onward. Tritium overflow was stimulated after 40 and 90 min (S1, S2) and the ratio of the overflow evoked by S2 over that evoked by S1 was determined; results are given as per cent of the S2/S1 values in B-HT 920-free controls. The S2/S1 values in the five B-HT 920-free control series were: 0.86±0.02 (no antagonist); 0.70±0.02 (haloperidol); 0.93±0.07 ((S)-nafadotride); 0.77±0.03 (ST-148); 0.78±0.03 (ST-198). Means±s.e.mean of 5–31 (B-HT 920 alone) and 4–7 independent superfusion experiments (in the presence of antagonists).

Figure 3.

Figure 3

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Effect of quinpirole on the electrically evoked tritium overflow from [3H]-noradrenaline-preincubated retinal discs and interaction with dopamine D2 receptor-selective antagonists. The antagonists were present throughout the superfusion (110 min), quinpirole from 62 min onward. Tritium overflow was stimulated after 40 and 90 min (S1, S2) and the ratio of the overflow evoked by S2 over that evoked by S1 was determined; results are given as per cent of the S2/S1 values in quinpirole-free controls. The S2/S1 values in the three quinpirole-free control series were: 0.86±0.02 (no antagonist); 0.73±0.02 (haloperidol); 0.75±0.07 (ST-148). Means±s.e.mean of 7–16 (quinpirole alone) and 4–8 independent superfusion experiments (in the presence of antagonists).

The electrically evoked tritium overflow (S2/S1) was inhibited by 96±1% and 99±1% by tetrodotoxin 1 μM or omission of Ca2+ ions, respectively (n=5–8). The dopamine receptor agonists B-HT 920 and quinpirole inhibited the S2/S1 value in a concentration-dependent manner (Figures 2 and 3). The effect of either agonist became significant from 1 μM onward and the maximum effect was obtained at 100 μM; the extent of inhibition obtained for B-HT 920 100 μM (82±1%; n=14) was significantly (P<0.005) higher than that obtained for quinpirole 100 μM (71±2%; n=14). The negative logarithm of the concentration causing the half-maximum inhibitory effect (pEC50) was 5.80 and 5.83 for B-HT 920 and quinpirole, respectively.

The concentration-response curve of B-HT 920 was shifted to the right by haloperidol 0.01 μM but not affected by the same concentration of (S)-nafadotride (Figure 2A). The novel antagonist ST-148 0.32 μM caused a dextral shift of the concentration-response curve of B-HT 920 whereas the same concentration of ST-198 failed to do so (Figure 2B). Haloperidol 0.01 μM and ST-148 0.32 μM also shifted to the right the concentration-response curve of the other dopamine agonist, quinpirole (Figure 3). The apparent pA2 values obtained for the dopamine receptor antagonists are listed in Table 2. Compound ST-148 0.32 μM by itself facilitated the evoked overflow (S1) by 15%, whereas the other antagonists had no significant effect (Table 1).

Table 2.

Apparent pA2 values of the antagonists under study at the dopamine autoreceptor in the guinea-pig retina and their pKi values at recombinant hD2- and hD3-receptors

graphic file with name 133-0704192t2.jpg

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Binding studies

Binding of [125I]-iodosulpride to hD2L and hD3 receptors expressed in CHO cells has been thoroughly characterized in the studies by Sokoloff et al. (1992) and Sautel et al. (1995) and the Ki values for haloperidol and (S)-nafadotride (Table 2) were taken from these studies. Table 2 also shows the Ki values for the novel dopamine receptor antagonists ST-148 and ST-198. Compared to haloperidol and (S)-nafadotride, ST-148 exhibits an improved selectivity for hD2L receptors and ST-198 has a higher preference for hD3 receptors, respectively.

Discussion

The aim of our study was to characterize the release-regulating dopamine autoreceptor in the guinea-pig retina. The guinea-pig retinal discs were preincubated with [3H]-noradrenaline, which is accumulated in dopaminergic cells in this avascular retina (Chase, 1982; Schlicker et al., 1996) (and not in postganglionic sympathetic neurones innervating the retinal vasculature, like in porcine retina; Schlicker et al., 1990). The electrically evoked tritium overflow, which is Ca2+ dependent and tetrodotoxin-sensitive, therefore represents quasi-physiological dopamine release (Schlicker et al., 1996). [3H]-Noradrenaline was employed instead of [3H]-dopamine itself because of the lower variability of the results (Schlicker et al., 1996). In all of the experiments, nomifensine 10 μM was used to block the dopamine transporter. The amount of dopamine release (expressed as stimulation-evoked tritium overflow divided by the tissue tritium content×100) was almost 20% and much higher than in our previous studies on guinea-pig retinal discs in which, however, a blocker of the dopamine transporter was omitted and/or a lower stimulation frequency and/or current strength were used (Schlicker et al., 1996; Schlicker & Kathmann, 1998).

The antagonistic effects of haloperidol, (S)-nafadotride, ST-148, and ST-198 were studied against quinpirole and B-HT 920. The latter is also a potent α2-adrenoceptor agonist but the possibility that this property contributes to its inhibitory effect on dopamine release could be excluded (effect of B-HT 920 not antagonized by the α-adrenoceptor antagonist phentolamine; unpublished results). Surprisingly, the maximum inhibitory effect of quinpirole was less marked than that of B-HT 920 (whereas the pEC50 values of both drugs were identical), suggesting that quinpirole acts as a partial agonist. This finding is reminiscent of the results obtained in the study by Wood et al. (2000) in which both agonists were examined at recombinant hD2 and hD3 receptors in microphysiometry studies.

To determine the dopamine receptor subtype involved in the inhibitory effect of B-HT 920 or quinpirole the apparent pA2 values of the four antagonists were compared to their pKi values at hD2L and hD3 receptors (binding studies with [125I]-iodosulpride on CHO cells) (Table 2). The apparent pA2 values underestimate the true antagonist affinity since the antagonist, under the experimental conditions of the present study, is competing not only with the exogenously added agonist (B-HT 920 or quinpirole) but also with endogenously released dopamine. This is e.g. shown by the fact that dopamine release was facilitated, probably by interruption of the tonical activation of the dopamine autoreceptor, by ST-148 (and by haloperidol 0.1 μM, i.e. a 10 fold higher concentration than that used in this study; unpublished results). Taking into account this phenomenon it may be appropriate to add 0.5 log units to the apparent pA2 value to get a more authentic estimate of the true affinity of the antagonists.

A look at Table 2 shows that the apparent pA2 (+0.5 log units) values of the antagonists with preference for D2 receptors (haloperidol, ST-148) and their pKi values at hD2 receptors agree well, suggesting the involvement of D2 receptors. In harmony with this view, the effect of B-HT 920 was not antagonized by the antagonists with preference for D3 receptors at concentrations exceeding their Ki values at hD3 receptors by a factor of about 30. For comparison of potencies and affinities one may use in addition the ratios of antagonists with differing selectivity profile (Trendelenburg et al., 1995). This approach also offers the advantage that the underestimation of the true antagonist dissociation constant is cancelled out. In Table 3 the four possible ratios between the antagonists with D2- and D3-receptor preference have been listed. Again the values suggest that the dopamine autoreceptor in the guinea-pig retina is a D2 receptor.

Table 3.

Comparison of the ratios of the KB values for the dopamine receptor antagonists obtained in release studies with the ratios of their Ki values obtained in binding sites.

graphic file with name 133-0704192t3.jpg

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One point of concern is that the functional dopamine autoreceptor has been examined in retinal discs from an experimental animal rather than from humans and that the gpD2 receptor (which, to the best of our knowledge, has not yet been cloned) may differ in its pharmacological properties from the hD2 receptor. In a recent study, Dubocovich et al. (1997) used a similar approach like in the present study, i.e. they compared the potencies of a series of compounds at the melatonin heteroreceptor causing inhibition of dopamine release in retinal discs from an experimental animal, the rabbit, with their affinities for recombinant human melatonin receptors. Since enough native human retinal tissue is hardly available one might try in the future to perform release experiments in post mortem human retinal tissue or in cultured human retinal cells.

In conclusion, (i) the release-regulating autoreceptor for dopamine in guinea-pig retinal discs belongs to the D2-subtype of the D2-subfamily of dopamine receptors; (ii) the newly synthesized antagonists ST-148 and ST-198 strongly differentiate between the hD2- and hD3-subtype of dopamine receptors, and (iii) quinpirole acts as a partial agonist at the guinea-pig dopamine D2 receptor in the retina.

Acknowledgments

This study was supported by grants from the Deutsche Forschungsgemeinschaft (GRK 246) (to B. Weber and E. Schlicker), the European Community (QLG4-CT-1999-00075), and the NIDA/NIH (1RO1 DA 115 34-01) (both to P. Sokoloff and H. Stark). We are grateful to D. Petri and Dr S. Perachon for their assistance and to the companies Hoechst, Thomae and Yamanouchi for gifts of drugs.

Abbreviations

B-HT 920

6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-amine

CHO

Chinese hamster ovary

PSS

physiological salt solution

S

electrical stimulation

ST-148

N-(4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl)-5-(dimethylamino)-naphthalene-1-sulphonamide

ST-198

N-(4-[1,2,3,4-tetrahydroisoquinolin-2-yl]-butyl)-3-phenylacrylamide

t

collection period in which basal tritium efflux was determined

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