Summary
Dopamine receptors subtypes were studied in homogenates from rat brain areas, mainly the corpus striatum, using the two highly selective ligands 3H-apomorphine and 3H-domperidone. The clearly biphasic inhibition of the specific binding of these two ligands by some agents allowed us to define four distinct classes of binding site. 3H-apomorphine labels two classes of site displaying a large difference in affinity for domperidone, i.e. class I sites well recognized (IC50=5 nM) and class II sites poorly recognized (IC50=10 μM). 3H-domperidone also labels two distinet classes of site displaying a large difference in affinity for apomorphine and dopamine, i.e. class III sites well recognized by these agents (IC50=5 and 35 nM, respectively) and class IV sites poorly recognized (IC50=790 nM and 14 μM, respectively). The two classes I and III represent a single pharmacological class of dopaminergic receptors (labelled by either 3H-apomorphine or 3H-domperidone) as indicated by 1) their almost identical pharmacological specificities (high correlation between K d or K i values for a variety of dopaminergic agonists and antagonists); 2) their similar capacity in striatum as well as in other brain regions; 3) the identical decrease in capacity following kainate lesions; 4) their similar sensitivity to GTP and thermal denaturation. Because the pharmacological specificity of these sites excludes the possibility that they represent the recognition sites of the dopamine-sensitive adenylate cyclase, i.e. D-1 receptors, we propose to term them D-2 receptors. Class II and IV sites also differ from D-1 receptors as shown by drug specificity and the effect of kainate. We propose to term class II sites D-3 receptors and class IV sites D-4 receptors.
D-2 receptors are characterised by a high affinity for both dopamine receptor agonists and antagonists (K i and K d values in the nM range). They are localised post-synaptically to dopaminergic terminals in the striatum as indicated by 1) their decreased number (−60%) following kainate lesions of intrinsic neurones, and 2) their increased number (+40%) after 6-OHDA-induced degeneration of dopaminergic neurones. The capacity of D-2 receptors is decreased by 80% in the presence of 25 μM GTP. The binding of ligands to D-2 receptors preicubated at 45°C decreases with a half-life of 10 min. D-2 receptors may mediate behavioral actions of apomorphine in low dosage which are easily antagonised by neuroleptics.
D-3 receptors appear to be, at least in part, autoreceptors: their number decreases in striatum after 6-OHDA lesions (−30%) and is not modified following kainate lesions. They are characterised by a high affinity (K i in the nM range) for dopaminergic agonists (except for bromocriptine) contrasting with a rather low affinity for antagonists. The pharmacologically homogeneous class of D-3 receptor appears heterogeneous regarding both localisation and regulation by GTP.
D-4 receptors are partly localised on intrastriatal neurones (−17% after kainate lesions, +17% following 6-OHDA lesions). However, the small change after kainate-induced lesions suggests that a significant fraction of D-4 receptors is localised on terminals from extrinsic neurones. D-4 receptors are characterised by a high affinity for dopamine receptor antagonists (K i in the nM range) contrasting with a relatively low affinity for agonists. The number of D-4 receptors increases after either GTP or heat denaturation, a change which probably corresponds to the decrease in D-2 receptors. D-4 receptors may mediate typical behavioral actions of apomorphine in moderate dosage.
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References
Albe-Fessard D, Stutinsky F, Libouban S (1971) Atlas stéréotaxique du diencéphale du rat blanc. Editions du CNRS, Paris
Ariëns EJ, Beld AJ, Rodrigues De Miranda JF, Simonis AM (1979) The pharmacon-receptor-effector concept: a basis for understanding the transmission of information in biological systems. In: O'Brien RD (ed) The receptors. A comprehensive treatise, vol 1. Plenum Press, New York, p 33
Baudry M, Martres MP, Schwartz JC (1978) 3H-Domperidone and 3H-pimozide: more specific ligands for dopamine receptors studied in vitro and in vivo. In: Usdin E, Kopin IJ, Barchas J (eds) Catecholamines: Basic and clinical frontiers, vol 1. Pergamon Press, New York, p 565
Baudry M, Martres MP, Schwartz JC (1979) 3H-Domperidone: a selective ligand for dopamine receptors. Naunyn-Schmiedeberg's Arch Pharmacol 308:231–237
Beld AJ, Kuijer B, Rodrigues De Miranda JF, Wouterse AC (1978) Ligand binding to dopamine-receptors: analysis and interpretation. Life Sci 23:489–494
Bennett JP (1978) Methods in binding studies. In: Yamamura HI, Enna SJ, Kuhar MJ (eds) Neurotransmitter receptor binding. Raven Press, New York, p 58
Buda M, Roussel B, Renaud B, Pujol JF (1975) Increase in tyrosine hydroxylase in the locus coeruleus of the rat brain after contralateral lesioning. Brain Res 93:564–569
Burt DR, Creese I, Snyder SH (1976) Properties of 3H-haloperidol and 3H-dopamine binding associated with dopamine receptors in calf brain membranes. Mol Pharmacol 12:800–812
Carlsson A (1975) Receptor-mediated control of dopamine metabolism. In: Usdin E, Bunney WE (eds) Pre-and postsynaptic receptors. Annual ACNP Meeting, Puerto Rico. Marcel Dekker, New York
Cheng YC, Prusoff WH (1973) Relationship between the inhibition constant (K i) and the concentration of inhibitor which causes 50 per cent of inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108
Chen TC, Cote TS, Kebabian JW (1980) Endogenous components of the striatum confer dopamine-sensitivity upon adenylate cyclase activity: the role of endogenous guanyl nucleotides. Brain Res 181:139–149
Christiansen J, Squires RF (1974) Antagonistic effects of apomorphine and haloperidol on rat striatal synaptosomal tyrosine hydroxylase. J Pharm Pharmacol 26:367–369
Clement-Cormier YC, George RJ (1979) Multiple dopamine binding sites: localization and biochemical characterization. J Neurochem 32:1061–1069
Costentin J, Protais P, Schwartz JC (1975) Rapid and dissociated changes in the sensitivities of different dopamine receptors in mouse brain. Nature 257:405–407
Coyle JT, Schwarcz R (1976) Lesion of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature 263:244–246
Creese I, Snyder SH (1978) 3H-Spiroperidol labels serotonin receptors in rat cerebral cortex and hippocampus. Eur J Pharmacol 49:201–202
Creese I, Snyder SH (1979) Nigrostriatal lesions enhance striatal 3H-apomorphine and 3H-spiroperidol binding. Eur J Pharmacol 56:277–281
Creese I, Burt DR, Snyder SH (1975) Dopamine receptor binding: differentiation of agonist and antagonist states with 3H-dopamine and 3H-haloperidol. Life Sci 17:993–1002
Creese I, Burt DR, Snyder SH (1977) Dopamine receptor binding enhancement accompanies lesion-induced behavioral supersensitivity. Science 197:596–598
Creese I, Prosser T, Snyder SH (1978) Dopamine receptor binding: specificity, localization and regulation by ions and guanyl nucleotides. Life Sci 23:495–500
Creese I, Stewart K, Snyder SH (1979a) Species variations in dopamine receptor binding. Eur J Pharmacol 60:55–66
Creese I, Usdin TB, Snyder SH (1979b) Dopamine receptor binding regulated by guanine nucleotides. Mol Pharmacol 16:69–76
Creese I, Usdin TB, Snyder SH (1979c) Guanine nucleotides distinguish between two dopamine receptors. Nature 278:577–578
Di Chiara G, Gessa GL (1978) Pharmacology and neurochemistry of apomorphine. Adv Pharmacol Chemother 15:87–160
Di Chiara G, Porceddu ML, Vargiu L, Argiolas A, Gessa GL (1976) Evidence for dopamine receptors mediating sedation in the mouse brain. Nature 264:564–567
Farnebo LO, Hambeger B (1971) Drug-induced changes in the release of 3H-monoamine from field stimulated rat brain slices. Acta Physiol Scand 371:35–44
Fields JZ, Reisine TD, Yamamura HI (1977) Biochemical demonstration of dopaminergic receptors in rat and human brain using (3H)spiroperidol. Brain Res 136:578–584
Glowinski J, Cheramy A (1978) Dendritic release of dopamine: its role in the control of nigrostriatal dopaminergic neurons. In: Kopin E, Barchas J (eds) Catecholamines: basic and clinical frontiers, vol 1. Pergamon Press, New York, p 231
Howlett DR, Nahorski SR (1980) Quantitative assessment of heterogeneous 3H-spiperone binding to rat neostriatum and frontal cortex. Life Sci 26:511–517
Iversen LL, Rogawski MA, Miller RJ (1976) Comparison of the effects of neuroleptic drugs on pre-and postsynaptic dopaminergic mechanisms in the rat striatum. Mol Pharmacol 12:251–262
Kebabian JW, Calne DB (1979) Multiple receptors for dopamine. Nature 277:93–96
König FR, Klippel RA (1970) The rat brain. A stereotaxic atlas. Krieger RE Publishing Co., INC, Tunthington, N.J.
Lew JY, Goldstein M (1979) Dopamine receptor binding for agonists and antagonists in thermal exposed membranes. Eur J Pharmacol 55:429–430
Leysen JE (1979) Unitary dopaminergic receptor composed of cooperatively linked agonist and antagonist sub-unit binding sites. Communic Psychopharmacol 3:397–410
Leysen JE, Gommeren W, Laduron PM (1978a) Spiperone: a ligand of choice for neuroleptic receptors. I. Kinetics and characteristics of in vitro binding. Biochem Pharmacol 27:307–316
Leysen JE, Niemegeers CJE, Tollenaere JP, Laduron PM (1978b) Serotonergic component of neuroleptic receptors. Nature 272:168–171
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Maj J, Przewlocka B, Kukulka L (1977) Sedative action of low doses of dopaminergic agents. Pol J Pharmacol Pharm 29:11–21
Martres MP, Costentin J, Baudry M, Marçais H, Protais P, Schwartz JC (1977) Long-term changes in the sensitivity of pre- and postsynaptic dopamine receptors in mouse striatum as evidenced by behavioral and biochemical studies. Brain Res 136:319–337
Martres MP, Baudry M, Schwartz JC (1978) Characterization of 3H-domperidone binding on striatal dopamine receptors. Life Sci 23:1781–1784
Moskal JR, Basu S (1975) The measurement of glutamate decarboxylase activity in brain tissues by a simple microradiometric method. An Biochem 65:449–457
Nagy JI, Lee T, Seeman P, Fibiger HC (1978) Direct evidence for presynaptic and postsynaptic receptors in brain. Nature 274:278–281
Nathanson JA, Greengard P (1977) “Second messengers” in the brain. Sci Am 237:108–119
Nieoullon A, Cheramy A, Glowinski J (1977) An adaptation of the push-pull cannula method to study the in vivo release of 3H-dopamine synthetized from 3H-tyrosine in cat caudate nucleus: effects of various physiocal and pharmacological treatments. J Neurochem 28:819–828
Parker RB, Waud DR (1971) Pharmacological estimation of drugreceptor dissociation constants. Statistical evaluation. I. Agonists. J Pharmacol Exp Ther 177:1–12
Protais P, Costentin J, Schwartz JC (1976) Climbing behavior induced by apomorphine in mice: a simple test for the study of dopamine receptors in striatum. Psychopharmacol 50:1–6
Puech AJ, Simon P, Boissier JR (1976) Antagonism by sulpiride of the apomorphine-induced effects in rodents. Eur J Pharmacol 36:439–441
Reimann W, Zumstein A, Jackisch R, Starke K, Hertting G (1979) Effect of extracellular dopamine on the release of dopamine in the rabbit caudate nucleus: evidence for a dopaminergic feedback inhibition. Naunyn-Schmiedeberg's Arch Pharmacol 306:53–60
Rodbell M (1980) The role of hormone receptors and GTP-regulatory proteins in membrane transduction. Nature 284:17–22
Roth RH (1979) Dopamine autoreceptors: pharmacology, function and comparison with post-synaptic dopamine receptors. Communic Psychopharmacol 3:429–445
Schwarcz R, Creese I, Coyle JT, Snyder SH (1978) Dopamine receptors labelled on cerebral cortical afferents to rat corpus striatum. Nature 271:766–768
Schwartz JC, Costentin J, Martres MP, Protais P, Baudry M (1978) Modulation of receptor mechanisms in the CNS: hyper- and hyposensitivity to catecholamines. Neuropharmacology 17:665–685
Seeman P, Chau-Wong M, Tedesco J, Wong K (1975) Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc Natl Acad Sci USA 72:4376–4380
Seeman P, Lee T, Chau-Wong M, Tedesco J, Wong K (1976) Dopamine receptors in human and calf brains, using (3H)-apomorphine and an antipsychotic drug. Proc Natl Acad Sci USA 73:4354–4358
Sokoloff P, Martres MP, Schwartz JC (1980) 3H-apomorphine labels both dopamine post-synaptic receptors and autoreceptors. Nature 288:283–286
Starke K, Reimann W, Zumstein A, Hertting G (1978) Effect of dopamine receptor agonists and antagonists on release of dopamine in the rabbit caudate nucleus in vitro. Naunyn-Schmiedeberg's Arch Pharmacol 305:27–36
Strömbom U (1976) Catecholamine receptor agonists. Effects on motor activity and rate of tyrosine hydroxylation in mouse brain. Naunyn-Schmiedeberg's Arch Pharmacol 292:167–176
Strömbom U (1977) Antagonism by haloperidol of locomotor depression induced by small doses of apomorphine. J Neural Transm 40:191–194
Titeler M, Seeman P (1979) Selective labeling of different dopamine receptors by a new agonist 3H-ligand: 3H-N-propylnorapo-morphine. Eur J Pharmacol 56:291–292
Titeler M, Weinreich P, Sinclair D, Seeman P (1978) Multiple receptors for brain dopamine. Proc Natl Acad Sci USA 75:1153–1156
Titeler M, List S, Seeman P (1979) High affinity dopamine receptors (D3) in rat brain. Communic Psychopharmacol 3:411–420
Versteeg DHG, Van Der Gusten J, De Jong W, Palkovits M (1976) Regional concentrations of noradrenaline and dopamine in rat brain. Brain Res 113:563–574
Walters JR, Roth RH (1976) Dopaminergic neurons: an in vivo system for measuring drug interactions with presynaptic receptors. Naunyn-Schmiedeberg's Arch Pharmacol 296:5–14
Watling KJ, Dowling JE, Iversen LL (1979) Dopamine receptors in the retina may all be linked to adenylate cyclase. Nature 281:578–580
Weinreich P, Seeman P (1980) Effect of kainic acid on striatal dipamine receptors. Brain Res 198:491–496
Wesifall TC, Besson MJ, Giorguieff MF, Glowinski J (1976) The role of presynaptic receptors in release and synthesis of 3H-dopamine by slices of rat striatum. Naunyn-Schmiedeberg's Arch Pharmacol 292:279–287
Zahniser NR, Molinoff PB (1978) Effect of guanine nucleotides on striatal dopamine receptors. Nature 275:453–455
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Sokoloff, P., Martres, M.P. & Schwartz, J.C. Three classes of dopamine receptor (D-2, D-3, D-4) identified by binding studies with 3H-apomorphine and 3H-domperidone. Naunyn-Schmiedeberg's Arch. Pharmacol. 315, 89–102 (1980). https://doi.org/10.1007/BF00499251
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DOI: https://doi.org/10.1007/BF00499251