Summary
Apomorphine antagonistic effects of a range of dopamine (DA) antagonists were studied after intracerebral and after peripheral injection. Inhibitory activity was found selectively within the ventral striatum with a D-1 antagonist (SCH 23390), D-2 antagonists (benzamides, butyrophenones) and mixed D-1/D-2 antagonists (thioxanthenes, phenothiazines), whereas α-adrenoceptor antagonists, muscarinic- and serotonin S2-antagonists were ineffective. Great differences in absolute potencies and in peripheral versus intrastriatal potency ratios were observed. High peripheral versus central selectivity ratios and high intrastriatal potencies were found with the hydrophilic compounds (-)-sulpiride, veralipride and domperidone which do not readily cross the blood-brain barrier. High intrastriatal potency was also observed for the benzamide, YM 09151-2, haloperidol and spiroperidol although these compounds had lower peripheral versus intrastriatal selectivity ratios. Neuroleptic potency after intracerebral administration did not depend solely on DA receptor affinity but additionally on physicochemical properties. On the basis of the peripheral vs. intrastriatal potency ratios, it is concluded that only few of the neuroleptics tested in this study are suited for topographical studies of DA receptor function using intracerebral injection but that (-)-sulpiride is one example combining high potency, high central selectivity, high DA D-2 receptor specificity stereoselectivity and long duration of action. The siteselectivity of apomorphine-antagonistic effects was further studied using (-)-sulpiride as a model compound. Inhibitory activity against oral stereotypy was preferentially found after injection into the ventral striatum, whereas the lowcomponent patterns of apomorphine stereotypy (sniffing, rearing, motility) were blocked equally well in the ventral striatum and nucleus accumbens. In contrast, a facilitation of oral stereotypy was induced by (-)-sulpiride in the dorsal striatum. No effect on apomorphine-stereotypy was found after injection into frontal cortex, supragenual cortex, septum, amygdala, substantia nigra or thalamus. These results support data obtained in lesion studies indicating the ventral striatum as the important site mediating inhibition of oral stereotypy after DA receptor blockade. However, the differentiation between striatum and accumbens in medition of stereotypy and hyperactivity was not as absolute as has been suggested by lesion studies
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References
Arnt J, Hyttel J (1984) Differential inhibition by dopamine D-1 and D-2 antagonists of circling behaviour induced by dopamine agonists in rats with unilateral 6-hydroxydopamine lesions. Eur J Pharmacol 102:349–354
Carter CJ, Pycock CJ (1980) Behavioural and biochemical effects of dopamine and noradrenaline depletion within the medial prefrontal cortex of the rat. Brain Res 192:163–176
Christensen AV, Arnt J, Hyttel J, Larsen JJ, Svendsen O (1984) Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics. Life Sci 34:1529–1540
Cools AR, vanRossum JM (1980) Multiple receptors for brain dopamine in behaviour regulation: Concept of dopamine-E and dopamine-I receptors. Life Sci 27:1237–1253
Costall B, Fortune DH, Naylor FJ (1979) Neuropharmacological studies on the neuroleptic potential of domperidone (R33812). J Pharm Pharmacol 31:344–347
Costall B, Naylor RJ (1980) Assessment of the test procedures used to analyse neuroleptic action. Rev. Pur Applied Pharmacological Sci 1:3–83
Costall B, De Souza CX, Naylor RJ (1980) Topographical analysis of the actions of 2-(N,N-dipropyl)amino-5,6-dihydroxytetralin to cause biting behaviour and locomotor hyperactivity form the striatum of the guinea-pig. Neuropharmacology 19:623–631
Costall B, Kelly ME, Naylor RJ (1983) The production of asymmetry and circling behaviour following unilateral, intrastriatal administration of neuropleptic agents: A comparison of abilities to antagonise striatal function. Eur J Pharmacol 96:79–86
Delini-Stula A, Bauman P, Büch O (1979) Depression of exploratory activity by clonidine in rats as a model for the detection of relative pre- and postsynaptic central noradrenergic receptor selectivity of α-adrenolytic drugs. Naunyn-Schmiedeberg's Arch Pharmacol 307:115–122
Fleminger S, Van de Waterbeemd H, Rupniak NMJ, Reavill C, Testa B, Jenner P, Marsden CD (1983) Potent lipophilic substituted benzamide drugs are not selective D-1 dopamine receptor antagonists in the rat. J Pharm Pharmacol 35:363–368
Fog R (1972) On stereotypy and catalepsy: Studies on the effect of amphetamines and neuroleptics in rats Acta Neurol Scand 48, suppl. 50
Honda F, Satoh Y, Shimomura K: Satoh H, Noguchi H, Uchida S, Kato R (1977) Dopamine receptor blocking activity of sulpiride in the central nervous system. Jpn J Pharmacol 27:397–411
Hyttel J (1980) Further evidence that 3H-cis(Z)-flupenthixol binds to the adenylate cyclase-associated dopamine receptor (D-1) in rat corpus striatum. Psychopharmacology 67:107–109
Hyttel J (1983) SCH 23390 — the first selective dopamine D-1 antagonist. Eur J Pharmacol 91:153–154
Hyttel J, Arnt J, Bøgesø KP (1984) Antipsychotic drugs: Configurational stereoisomers. In: Smith DF (ed) CRC Handbook of stereoisomers: Drugs in psychopharmacology. CRC Press Inc, Forida, p 143
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
Iversen SD, Koob GF (1977) Behavioural implications of dopaminergic neurones in the mesolimbic system. In: Costa E, Gessa GL (eds) Advances in biochemical psychopharmacology, vol 16. Raven Press, New York, pp 209–214
Joyce JN (1983) Multiple dopamine receptors and behaviour. Neuroscience Biobehavioral Reviews 7:227–256
Kebabian JW, Calne DB (1979) Multiple receptors for dopamine. Nature 277:93–96
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
König JFR, Klippel RA (1963) The rat brain. Williams and Wilkins, Baltimore
Leysen JE, Awouters F, Kennis L, Laduron PM, Vandenberk J, Janssen PAJ (1981) Receptor binding profile of R 41468, a novel antagonist at 5-HT2 receptors. Life Sci 28:1015–1022
Massingham R, Dubocovich ML, Shepperson NB, Langer SZ (1981) In vivo selectivity of prazosin but not of WB 4101 for postsynaptic alpha-1 adrenoceptors. J Pharmacol Exp Ther 217:467–474
Niemegeers CJE, Janssen PAJ (1979) A systematic study of the pharmacological activities of dopamine antagonists. Life Sci 24:2201–2216
Peroutka SJ, Snyder SH (1980) Relationship of neuroleptic drug effects at brain dopamine, serotonin, ]ga-adrenergic, and histamine receptors to clinical potency. Am J Psychiatr 137:1518–1522
Perrault G, Margarit J, Laville C (1981) Proprietés antidopaminergiques centrales comparées due véralipride et du sulpiride. Rev Fr Gynécol Obstét 76:655–660
Petty F, Mott J, Sherman AD (1984) Potentical locus and mechanism of blockade of conditioned avoidance responding by neuroleptics. Neuropharmacology 23:73–78
Pijnenburg AJJ, Honig WMM, Van Rossum JM (1975) Antagonism of apomorphine- and d-amphetamine-induced stereotyped behaviour by injection of low doses of haloperidol into the caudate nucleus and the nucleus accumbens. Psychopharmacologia (Berl) 45:65–71
Scheel-Krüger J (1983) The GABA receptor and animal behavior. Evidence that GABA transmits and mediates dopaminergic functions in the basal ganglia and the limbic system. In: Enna SJ (ed) The GABA-receptors. The Humana Press, Clifton, New Jersey, p 215
Scheel-Krüger J, Arnt J (1985) New aspects on the role of dopamine, acetylcholine and GABA for the development of tardive dyskinesia. In: Casey D, Chase TN, Christensen AV, Gerlach J (eds) Dyskinesia — research and treatment. Springer, Berlin Heidelberg New York
Seeman P (1981) Brain dopamine receptors. Pharmacological Reviews 32:229–313
Siegel S (1956) Nonparametric statistics for the behavioral sciences. McGraw-Hill, New York
Terai M, Usuda S, Kuroiwa I, Noshiro O, Maeno H (1983) Selective binding YM-09151-2, a new potent neuroleptic, to D2-dopaminergic receptors. Jpn J Pharmacol 33:749–755
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Arnt, J. Antistereotypic effects of dopamine D-1 and D-2 antagonists after intrastriatal injection in rats. pharmacological and regional specificity. Naunyn-Schmiedeberg's Arch. Pharmacol. 330, 97–104 (1985). https://doi.org/10.1007/BF00499901
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DOI: https://doi.org/10.1007/BF00499901