Summary
A series of in vivo experiments were undertaken, relating functional (motor activity, body temperature), dopamine (DA) receptor binding and neurochemical (catecholamine synthesis and utilization, DA release) aspects of the pharmacology of SCH 23390 in the rat.
The compound inhibited the locomotor hyperactivity, but not the hypothermia, induced by the potent DA stimulant DP-5,6-ADTN. Interstingly, SCH 23390 simultaneously failed to displace DP-5,6-ADTN from its binding sites in the rat striatum—used as a direct in vivo biochemical index of DA (D-2) receptor interaction. The spontaneous locomotion in non-pretreated rats was likewise inhibited by SCH 23390. The locomotor-suppressive action, but not the DP-5,6-ADTN-displacing capcity of the D-2 blocker haloperidol was significantly enhanced by SCH 23390, suggesting that motility can be suppressed by either enhanced D-1 or D-2 (postsynaptic) receptor blockade, but also that the D-1 and D-2 sites involved may be physically distinct.
SCH 23390 only slightly altered in vivo neurochemical of DA synthesis, release and nerve-impulse flow, indicating that, while similar in suppressing dopaminergic behaviour, the D-1 antagonist is less effective than traditional neuroleptics as an activator of DA neuronal feedback mechanisms. The weak increases of DA synthesis and release nonetheless obtained were equal in magnitude (30–40%) in the limbic vs. striatal brain areas; also in this respect, SCH 23390 thus differs from classical neuroleptics, which generally display more marked effects in the striatum than in limbic tissue.
No major changes in the in vivo indices of NA synthesis and utilization (or in 5-HT synthesis) were found after SCH 23390 administration, by and large supporting the DA receptor specificity of the compound.
In summary, the studies demonstrated that SCH 23390 can offset and accentuate, respectively, behavioural consequences of D-2 receptor stimulation and blockade. Importantly, at the same time no direct interaction at the level of D-2 DA receptor sites in the striatum was detected. Only slight, D-2 antagonist-like, changes in neurochemical indices of dopaminergic activity were observed after D-1 receptor blockade by means of SCH 23390. With regard to DA agonist hypothermia, SCH 23390 was without effect per se, but (at a high dose) attenuated the action of the D-2 antagonist haloperidol. The observations may indicate that the complex interactions between central D-1 and D-2 receptor-controlled mechanisms that influence behaviour, neurochemistry, and possibly autonomic nervous expression, are not identical.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Andén N-E (1980) Regulation of monoamine synthesis and utilization by receptors. In: Szekeres L (ed) Handbook of experimental pharmacology. Springer, Berlin Heidelberg New York, pp 429–462
Arnt J, Hyttel J (1985) Differential involvement of dopamine D-1 and D-2 receptors in the circling behaviour induced by apomorphine, SK & F 38393, pergolide, and LY 171555 in 6-hydroxydopamine-lesioned rats. Psychopharmacology 85: 346–352
Barone P, Davis TA, Braun AR, Chase TN (1986) Dopaminergic mechanisms and motor function: characterization of D-1 and D-2 dopamine receptor interactions. Eur J Pharmacol 123: 109–114
Beaulieu M, Itoh Y, Tepper P, Horn AS, Kebabian JW (1984) N, N-disubstituted 2-aminotetralins are potent D-2 dopamine receptor agonists. Eur J Pharmacol 105: 15–21
Bischoff S, Heinrich M, Sonntag HM, Krauss J (1986) The D-1 dopamine receptor antagonist SCH 23390 also interacts potently with brain serotonin (5-HT2) receptors. Eur J Pharmacol 129: 367–370
Carboni E, Longoni R, Deidda S, di Chiara G (1986) SCH 23390 antagonizes apomorphine- and ergot-induced hypothermia. Eur J Pharmacol 125: 17–22
Carlson JH, Bergstrom DA, Walters JR (1986) Neurophysiological evidence that D-1 dopamine receptor blockade attenuates postsynaptic but not autoreceptor-mediated effects of dopamine agonists. Eur J Pharmacol 123: 237–251
Carlsson A (1978) Mechanism of action of neuroleptic drugs. In: Lipton MA, DiMascio A, Killam KF (eds) Psychopharmacology: a generation of progress. Raven Press, New York, pp 1057–1070
Carlsson A, Davis JN, Kehr W, Lindquist M, Atack C (1972) Simultaneous measurement of tyrosine and tryptophan hydroxylase activities in brain in vivo using an inhibitor of the aromatic amino acid decarboxylase. Naunyn Schmiedebergs Arch Pharmacol 275: 153–168
Carlsson A, Löfberg L (1985) In vivo displacement by 3-PPP enantiomers of N,N-dipropyl-5,6-ADTN from dopamine receptor-binding sites in rat striatum. J Neural Transm 64: 173–185
Christensen AV, Arnt J, Hyttel J, Larsen J-J, Svendsen O (1984) Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics. Life Sci 34: 1529–1540
Clark WG (1979) Changes in body temperature after administration of amino acids, peptides, dopamine, neuroleptics and related agents. Neurosci Biobehav Rev 3: 179–231
Cross AJ, Mashal RD, Johnson JA, Owen F (1983) Preferential inhibition of ligand binding to calf striatal dopamine D-1 receptors by SCH 23390. Neuropharmacology 22: 1327–1329
Feenstra MGP (1984) Dopamine receptor agonists. Neuropharmacological and bioanalytical evaluation. Thesis, Rijksuniversiteit, Groningen, The Netherlands
Feenstra MGP, Rollema H, Mulder TBA, de Vries JB, Horn AS (1983a) In vivo dopamine receptor agonist binding in rat brain: relation with pharmacological effects. Eur J Pharmacol 90: 433–436
Feenstra MGP, Rollema H, Mulder TBA, Westerink BHC, Horn AS (1983b) In vivo dopamine receptor binding studies with a non-radioactively labeled agonist, dipropyl-5,6-ADTN. Life Sci 32: 1313–1323
Gershanik O, Heikkila RE, Duvoisin RC (1984) Behavioral correlations of dopamine receptor activation. Neurology 33: 1489–1492
Hjorth S (1983) On the mode of action of 3-(3-hydroxyphenyl-N-n-propylpiperidine, 3-PPP, and its enantiomers. (Thesis). Acta Physiol Scand 118 [Suppl 517]: 1–52
Hjorth S, Carlsson A, Clark D, Svensson K, Wikström H, Sanchez D, Lindberg P, Hacksell U, Arvidsson L-E, Johansson A, Nilsson JLG (1983) Central dopamine receptor agonist and antagonist actions of the enantiomers of 3-PPP. Psychopharmacology 81: 89–99
Hjorth S, Svensson K, Carlsson A, Wikström H, Andersson B (1986) Central dopaminergic properties of HW-165 and its enantiomers:trans-octahydrobenzo(f)quinoline congeners to 3-PPP. Naunyn Schmiedebergs Arch Pharmacol 333: 205–218
Hyttel J (1983) SCH 23390-the first selective dopamine D-1 antagonist. Eur J Pharmacol 91: 153–154
Hyttel J (1984) Functional evidence for selective dopamine D-1 receptor blockade by SCH 23390. Neuropharmacology 23: 1395–1401
Iorio LC, Barnett A, Leitz FH, Houser VP, Korduba CA (1983) SCH 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems. J Pharmacol Exp Ther 226: 462–468
Itoh Y, Goldman ME, Kebabian JW (1984) TL 333, a benzhydro(g)quinoline, stimulates both D-1 and D-2 dopamine receptors: implications for the selectivity of LY 141865 towards the D-2 receptor. Eur J Pharmacol 108: 99–101
Kehr W (1976) 3-Methoxytyramine as an indicator of impulse-induced dopamine release in rat brain in vivo. Naunyn Schmiedebergs Arch Pharmacol 293: 209–215
Mailman RB, Schulz DW, Lewis MH, Staples L, Rollema H, DeHaven DL (1984) SCH 23390: a selective D-1 dopamine antagonist with potent D-2 behavioural actions. Eur J Pharmacol 101: 159–160
Mailman RB, Schulz DW, Kilts CD, Lewis MH, Rollema H, Wyrick S (1986) Multiple forms of the D1 dopamine receptor: its linkage to adenylate cyclase and psychopharmacological effects. Psychopharmacol Bull 22: 593–597
Mereu GP, Collu M, Ongini E, Biggio G, Gessa GL (1985) SCH 23390, a selective dopamine D-1 antagonist, activates dopamine neurons but fails to prevent their inhibition by apomorphine. Eur J Pharmacol 111: 393–396
Mulder TBA, Grol CJ, Dijkstra D, Horn AS (1985) Kinetic and pharmacological profiles of the in vitro binding of the potent dopamine agonist (3H)N,N-dipropyl-5,6-dihydroxy-2-aminotetralin to rat striatal membranes. Eur J Pharmacol 112: 73–79
Ohno Y, Sasa M, Takaori S (1985) Dopamine D-2 receptor-mediated excitation of caudate nucleus neurons from the substantia nigra. Life Sci 37: 1515–1521
Ohno Y, Sasa M, Takaori S (1986) Excitation by dopamine D-2 receptor agonists, bromocriptine and LY 171555, in caudate nucleus neurons activated by nigral stimulation. Life Sci 38: 1867–1873
Onali PL, Mereu G, Olianas MC, Bunse B, Rossetti Z, Gessa GL (1985) SCH 23390, a selective D1 dopamine receptor blocker enhances the firing rate of nigral dopaminergic neurons but fails to activate striatal tyrosine hydroxylase. Brain Res 340: 1–7
Plantjé JF, Daus FJ, Hansen HA, Stoof JC (1984) SCH 23390 blocks D-1 and D-2 dopamine receptors in rat neostriatum in vitro. Naunyn Schmiedebergs Arch Pharmacol 327: 180–182
Rollema H, Feenstra MGP, Grol CJ, Lewis MH, Staples L, Mailman RB (1986) S(−)-DP-5,6-ADTN as an in vivo dopamine receptor ligand: relation between displacement by dopamine agonists and their pharmacological effects. Naunyn Schmiedebergs Arch Pharmacol 332: 338–345
Saller CF, Salama AI (1986) D-1 and D-2 dopamine receptor blockade: interactive effects in vitro and in vivo. J Pharmacol Exp Ther 236: 714–720
Seeman P (1980) Brain dopamine receptors. Pharmacol Rev 32: 29–313
Setler PE, Sarau HM, Zirkle CL, Saunders HL (1978) The central effects of a novel dopamine agonist. Eur J Pharmacol 50: 419–430
Stoof JC, Kebabian JW 61984) Two dopamine receptors: biochemistry, physiology and pharmacology. Life Sci 35: 2281–2286
Zetterström T, Sharp T, Ungerstedt U (1986) Effect of dopamine D-1 and D-2 receptor selective drugs on dopamine release and metabolism in rat striatum in vivo. Naunyn Schmiedebergs Arch Pharmacol 334: 117–124
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hjorth, S., Carlsson, A. In vivo receptor binding, neurochemical and functional studies with the dopamine D-1 receptor antagonist SCH 23390. J. Neural Transmission 72, 83–97 (1988). https://doi.org/10.1007/BF01250232
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01250232