Summary
Functional interactions between dopamine receptor subtypes may affect behavioral and biochemical responses which serve as models for neuropsychiatric illnesses and the clinical effects of drug therapy. We evaluated the effects of chronic exposure to the selective D1 receptor antagonist SCH 23390, and the selective D2 receptor antagonist metoclopramide, on spontaneous and drug-induced behavior and receptor density in rats, and then determined how these effects would be modified by concurrent administration of antagonists or agonists [SKF 38393, LY 171555 (quinpirole)] selective for the complementary receptor subtype. Administered alone, both the D1 and D2 antagonists had acute cataleptic effects to which animals became tolerant following chronic treatment, but the selective antagonists had opposing effects on spontaneous locomotor activity. Both antagonists produced equivalent, supersensitive behavioral responses to apomorphine, and resulted in an increase in D2 receptor density. Coadministration of the D1 and D2 antagonists had a synergistic effect on catalepsy, attenuated the effects on spontaneous locomotor activity observed with either drug alone, and had an additive effect on both apomorphine-induced stereotypic behavior and D2 receptor proliferation. On the other hand, when either selective antagonist was combined with the agonist selective for the complementary receptor subtype, both D2 receptor proliferation and behavioral supersensitivity were completely blocked. Combined antagonist-agonist treatments had opposing effects on the development of tolerance to antagonist-induced catalepsy. D2 —but not D1 — receptor densities were correlated with animals' behavioral responses to apomorphine. There results support and extend the notion that complex functional interactions between D1 and D2 receptor families occur within the central nervous system, and suggest that novel effects might be derived from combined administration of receptor selective agonists and antagonists.
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References
Ant J, Perregaard J (1987) Synergistic interaction between dopamine D-1 and D-2 receptor agonists: circling behaviour of rats with hemitransection. Eur J Pharmacol 143: 45–53
Arnt J, Hyttel J, Perregaard J (1987) Dopamine D-1 receptor agonists combined with the selective D-2 agonist quinpirole facilitate the expression of oral stereotyped behaviour in rats. Eur J Pharmacol 133: 137–145
Bedard PJ, Gomez-Mancilla B, Blanchette P, Gagnon C, Falardeau P, DiPaolo T (1993) Role of selective D1 and D2 agonists in inducing dyskinesia in drug-naive MPTP monkeys. In: Narabayaski H, Nagatsu T, Yanagisawa N, Mizuno Y (eds) Advances in neurology, vol 60. Raven Press, New York, pp 113–118
Billard W, Ruperto V, Crosby G, Iorio LC, Barnett A (1984) Characterization of the binding of [3H]SCH23390, a selective D1 receptor antagonist ligand, in rat striatum. Life Sci 35: 1885–1893
Boyson SJ, McGonigle P, Molinoff PB (1986) Quantitative autoradiographic localization of the D1 and D2 subtypes of dopamine receptors in rat brain. J Neurosci 6: 3177–3188
Braun AR, Chase TN (1986) Obligatory D-1/D-2 receptor interaction in the generation of dopamine agonist related behaviors. Eur J Pharmacol 131: 301–306
Braun AR, Chase TN (1988) Behavioral effects of chronic exposure to selective D-1 and D-2 dopamine receptor agonists [published erratum appears in Eur J Pharmacol 154(3): 351–2]. Eur J Pharmacol 147: 441–451
Campbell A, Baldessarini RJ, Neumeyer JL (1993) Altered spontaneous behavior and sensitivity to apomorphine in rats following pretreatment with S(+)-aporphines or fluphenazine. Psychopharmacology 111: 351–358
Cheetham SC, Kettle CJ, Martin KF, Heal DJ (1995) D1 receptor binding in rat striatum: modification by various D1 and D2 antagonists, but not by sibutramine hydrochloride, antidepressants or treatments which enhance central dopaminergic function. J Neural Transm [Gen Sect] 102: 35–46
Chipkin RE, McQuade RD, Iorio LC (1987) D1 and D2 binding site upregulation and apomorphine-induced stereotypy. Pharmacol Biochem Behav 28: 477–482
Costall B, Naylor RJ (1975) The behavioural effects of dopamine applied intracerebrally to areas of the mesolimbic system. Eur J Pharmacol 32: 87–92
Duffy RA, Kaminska G, Chipkin RE, McQuade RD (1992) Selective upregulation of D-1 dopamine receptors following chronic administration of SCH 39166 in primates. Pharmacol Biochem Behav 41: 235–238
Elliott PJ, Close SP, Walsh DM, Hayes AG, Marriott AS (1990) Neuroleptic-induced catalepsy as a model of Parkinson's disease. II. Effect of glutamate antagonists. J Neural Transm [PD Sect] 2: 91–100
Esposito E, Bunney BS (1989) The effect of acute and chronic treatment with SCH 23390 on the spontaneous activity of midbrain dopamine neurons. Eur J Pharmacol 169: 61–66
Gerfen CR (1992) The neostriatal mosaic: multiple levels of compartmental organization. J Neural Transm [Suppl] 36: 43–59
Gerfen CR, Engber TM (1992) Molecular neuroanatomic mechanisms of Parkinson's disease: a proposed therapeutic approach. Neurol Clin 10: 435–449
Giorgi O, Pibiri MG, Loi R, Corda MG (1993) Chronic treatment with SCH 23390 increases the production rate of dopamine D1 receptors in the nigrostriatal system of the rat. Eur J Pharmacol 245: 139–145
Gomez-Mancilla B, Bedard PJ (1991) Effect of D1 and D2 agonists and antagonists on dyskinesia produced by L-dopa in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys. J Pharmacol Exp Ther 259: 409–413
Grebb JA, Girault JA, Ehrlich M, Greengard P (1990) Chronic treatment of rats with SCH-23390 or raclopride does not affect the concentrations of DARPP-32 or its mRNA in dopamine-innervated brain regions. J Neurochem 55: 204–207
Groppetti A, Flauto C, Parati E, Vescovi A, Rusconi L, Parenti M (1986) Dopamine receptor changes in response to prolonged treatment with L-dopa. J Neural Transm 22: 33–40
Hallett M (1993) Physiology of basal ganglia disorders: an overview. Can J Neurol Sci 20: 177–183
Hess EJ, Albers LJ, Le H, Creese I (1986) Effects of chronic SCH23390 treatment on the biochemical and behavioral properties of D1 and D2 dopamine receptors: potentiated behavioral responses to a D2 dopamine agonist after selective D1 dopamine receptor upregulation. J Pharmacol Exp Ther 238: 846–854
Hess EJ, Norman AB, Creese I (1988) Chronic treatment with dopamine receptor antagonists: behavioral and pharmacologie effects on D1 and D2 dopamine receptors. J Neurosci 8: 2361–2370
Hornykiewicz O (1975) Parkinsonism induced by dopaminergic antagonists. Adv Neurol 9: 155–164
Janssen PA, Awouters FH (1994) Is it possible to predict the clinical effects of neuroleptics from animal data? Part V. From haloperidol and pipamperone to risperidone. Arzneimittelforschung 44: 269–277
Janssen PA, Niemegeers CJ, Schellekens KH (1966) Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data? Arzneimittelforschung 16: 339–246
Jenner P, Kerwin R, Rupniak NM, Murugaiah K, Hall MD, Fleminger S, Marsden CD (1983) Long-term adaptive changes in striatal dopamine function in response to chronic neuroleptic intake in rats. J Neural Transm [Suppl] 18: 205–212
Jenner P, Rupniak NM, Marsden CD (1985) Differential alteration of striatal D-1 and D-2 receptors induced by the long term administration of haloperidol, sulpride or clozapine to rats. Psychopharmacology [Suppl] 2: 174–181
Kelly PH, Seviour PW, Iversen SD (1975) Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Brain Res 94: 507–522
Klawans HL, Goetz CG, Carvey PM (1983) Animals models of tardive dyskinesia. Clin Neuropharmacol 6: 129–135
LaHoste GJ, Marshall JF (1989) Non-additivity of D2 receptor proliferation induced by dopamine denervation and chronic selective antagonist administration: evidence from quantitative autoradiography indicates a single mechanism of action. Brain Res 502: 223–232
LaHoste GJ, Marshall JF (1991) Chronic eticlopride and dopamine denervation induce equal nonadditive increases in striatal D2 receptor density: autoradiographic evidence against the dual mechanism hypothesis. Neuroscience 41: 473–481
LaHoste GJ, Marshall JF (1992) Dopamine supersensitivity and D1/D2 synergism are unrelated to changes in striatal receptor density. Synapse 12: 14–26
Lappalainen J, Hietala J, Koulu M, Seppala T, Sjoholm B, Syvalahti E (1990) Chronic treatment with SCH 23390 and haloperidol: effects on dopaminergic and serotonergic mechanisms in rat brain. J Pharmacol Exp Ther 252: 845–852
Lappalainen J, Hietala J, Pohjalainen T, Syvalahti E (1992) Regulation of dopamine D1 receptors by chronic administration of structurally different D1 receptor antagonists: a quantitative autoradiographic study. Eur J Pharmacol 210: 195–200
Laruelle M, Jaskiw GE, Lipska BK, Kolachana B, Casanova MF, Kleinman JE, Weinberger DR (1992) D1 and D2 receptor modulation in rat striatum and nucleus accumbens after subchronic and chronic haloperidol treatment. Brain Res 575: 47–56
Leysen JE, Gommeren W, Laduron PM (1978) Spiperone, a ligand of choice for neuroleptic receptors. Kinetics and characterization of in vitro binding. Biochem Pharmacol 27: 307–316
Lowry OH, Rosebrough NJ, Farr AJ, Randall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 163: 265–275
Lublin H, Gerlach J, Peacock L (1993) Chronic treatment with the D1 receptor antagonist, SCH 23390, and the D2 receptor antagonist, raclopride, in cebus monkeys withdrawn from previous haloperidol treatment. Extrapyramidal syndromes and dopaminergic supersensitivity. Psychopharmacology (Berl) 112: 389–397
Marin C, Chase TN (1993) Dopamine D1 receptor stimulation but not dopamine D2 receptor stimulation attenuates haloperidol-induced behavioral supersensitivity and receptor up-regulation. Eur J Pharmacol 231: 191–196
Marin C, Parashos SA, Kapitzoglou-Logothetis V, Peppe A, Chase TN (1993) D1 and D2 dopamine receptor-mediated mechanisms and behavioral supersensitivity. Pharmacol Biochem Behav 45: 195–200
Martin-Iverson MT (1991) Chronic treatment with D1 and D2 dopamine receptor agonists: combined treatments interact to differentially affect brain levels of monoamines. Naunyn Schmiedebergs Arch Pharmacol 344: 281–285
Mashurano M, Waddington JL (1986) Stereotyped behaviour in response to the selective D-2 dopamine receptor agonist RU 24213 is enhanced by pretreatment with the selective D-1 agonist SK&F 38393. Neuropharmacology 25: 947–949
McGeer PL, McGeer EG, Schurer U, Singh KA (1977) A glutaminergic corticostriatal path. Brain Res 128: 369–373
McGonigle P, Boyson SJ, Reuter S, Molinoff PB (1989) Effects of chronic treatment with selective and nonselective antagonists on the subtypes of dopamine receptors. Synapse 3: 74–82
Memo M, Pizzi M, Nisoli E, Missale C, Carruba MO, Spano P (1987) Repeated administration of (−)sulpride and SCH 23390 differentially up-regulate D-1 and D-2 dopamine receptor function in rat mesostriatal areas but not in corticallimbic brain regions. Eur J Pharmacol 138: 45–51
Meyer ME, Cottrell GA, Van Hartesveldt C (1992) Dopamine D1 antagonists potentiate the durations of bar and cling catalepsy and the dorsal immobility response in rats. Pharmacol Biochem Behav 41: 507–510
Molloy AG, Waddington JL (1988) Behavioural responses to the selective D1-dopamine receptor agonist R-SK&F 38393 and the selective D2-agonist RU 24213 in young compared with aged rats. Br J Pharmacol 95: 335–342
Murugaiah K, Fleminger S, Hall MD, Theodorou A, Jenner P, Marsden CD (1984) Alterations in different populations of striatal dopamnine receptors produced by 18 months continuous administration of cis- or trans-flupenthixol to rats. Neuropharmacology 23: 599–609
Parashos SA, Barone P, Tucci I, Chase TN (1987) Attenuation of D-1 antagonist-induced D-1 receptor upregulation by concomitant D-2 receptor blockade. Life Sci 41: 2279–2284
Parashos SA, Barone P, Marin CA, Paraschos AJ, Kapitzoglou-Logothetis V, Chase TN (1989) Haloperidol- and SCH23390-induced dopaminergic supersensitivities are not additive in the rat. Psychopharmacology (Berl) 98: 189–192
Parashos SA, Marin C, Chase TN (1989) Synergy between a selective D1 antagonist and a selective D2 antagonist in the induction of catalepsy. Neurosci Lett 105: 169–173
Parashos SA, Marin C, Barone P, Kapitzoglou-Logothetis V, Chase TN (1990) Effect of chronic D-1 and/or D-2 dopamine antagonist treatment on SKF 38393-induced non-stereotyped grooming. Psychopharmacology (Berl) 102: 411–413
Parenti M, Flauto C, Parati E, Vescovi A, Groppetti A (1986) Differential effect of repeated treatment with L-dopa on dopamine D-1 of D-2 receptors. Neuropharmacology 25: 331–337
Paul ML, Graybiel AM, David JC, Robertson HA (1992) D1-like and D2-like dopamine receptors synergistically activate rotation and c-fos expression in the dopamine-depleted striatum in a rat model of Parkinson's disease. J Neurosci 12: 3729–3742
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, Orlando
Robbins TW, Koob GF (1985) Selective disruption of displacement behavior by lesions of the mesolimbic dopamine system. Nature 285: 409
Sanberg PR, Bunsey MD, Giordano M, Norman AB (1988) The catalepsy test: its ups and downs. Behav Neurosci 102: 748–759
Schettini G, Ventra C, Florio T, Grimaldi M, Meucci O, Marino A (1992) Modulation by GTP of basal and agonist-stimulated striatal adenylate cyclase activity following chronic blockade of D1 and D2 dopamine receptors: involvement of G proteins in the development of receptor supersensitivity. J Neurochem 59: 1667–1674
See RE, Aravagiri M, Ellison GD (1989) Chronic neuroleptic treatment in rats produces persisting changes in GABAA and dopamine D-2, but not dopamine D-1 receptors. Life Sci 44: 229–236
Seeman P, Niznik HB (1990) Dopamine receptors and transporters in Parkinson's disease and schizophrenia. FASEB J 4: 2737–2744
Seeman P, Bzowej NH, Guan HC, Bergeron C, Reynolds GP, Bird ED, Riederer P, Jellinger K, Tourtellotte WW (1987) Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's, and Huntington's diseases. Neuropsychopharmacology 1: 5–15
Seeman P, Niznik HB, Guan HC, Booth G, Ulpian C (1989) Link between D1 and D2 dopamine receptors is reduced in schizophrenia and Huntington diseased brain. Proc Natl Acad Sci USA 86: 10156–10160
Smialowski A (1989) Chronic administration of SCH 23390 enhances spontaneous searching and locomotor activity of rats. An open field study. Behav Brain Res 35: 41–44
Stefanini E, Frau M, Gessa GL (1991) Increase in D2 dopamine receptors in the substantia nigra after chronic (−)-sulpiride treatment. Brain Res 555: 340–342
Stoof JC, Kebabian JW (1981) Opposing roles for D1 and D2 dopamine receptors in efflux of cyclic AMP from rat neostriatum. Nature 294: 366–368
Vaccheri A, DallÓlio R, Gandolfi O, Roncada P, Montanaro N (1987) Enhanced stereotyped response to apomorphine after chronic D-1 blockade with SCH 23390. Psychopharmacology 91: 394–396
Verma A, Kulkarni SK (1992) D1/D2 dopamine and N-methyl-D-aspartate (NMDA) receptor participation in experimental catalepsy in rats. Psychopharmacology 109: 477–483
Waddington JL, Gamble SJ (1980) Neuroleptic treatment for a substantial proportion of adult life: behavioral sequallae of 9 months haloperidol administration. Eur J Pharmacol 67: 363–369
Walters JR, Bergstrom DA, Carlson JH, Chase TN, Braun AR (1987) D1 dopamine receptor activation required for postsynaptic expression of D2 agonist effects. Science 236: 719–722
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Braun, A.R., Laruelle, M. & Mouradian, M.M. Interactions between D1 and D2 dopamine receptor family agonists and antagonists: the effects of chronic exposure on behavior and receptor binding in rats and their clinical implications. J. Neural Transmission 104, 341–362 (1997). https://doi.org/10.1007/BF01277656
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DOI: https://doi.org/10.1007/BF01277656