Summary
The effects of dopamine (DA) antagonists upon DA synthesis and utilisation in the rat striatum, olfactory tubercle and substantia nigra have been studied. The concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the rate of depletion of DA afterin vivo inhibition of tyrosine hydroxylase by H 44/68, and the accumulation of L-DOPA afterin vivo inhibition of 1-aromatic amino acid decarboxylase by NSD 1015 were measured in the study. Haloperidol (0.23μmol/kg i. p.), sulpiride (293μmol/kg i. p.) and remoxipride (5.6μmol/kg i. p.) increased both DA synthesis and utilisation in the striatum and olfactory tubercle. A lower dose of sulpiride (45μmol/kg i. p.) increased DA synthesis and utilisation in the olfactory tubercle alone. None of the compounds, at the doses used, affected either DOPAC and HVA concentrations or the rate of utilisation of DA in the substantia nigra. Sulpiride (293μmol/kg i. p.) and remoxipride, however, produced a modest rise in nigral DA synthesis. The dopamine D 1-selective antagonist SCH 23390 had only modest effects on striatal, limbic and nigral DA synthesis and utilisation at the doses tested (0.078 and 0.36μmol/kg i. p.).
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References
Andén N-E, Grabowska-Andén M (1985) Synthesis and utilization of catecholamines in the rat superior cervical ganglion following changes in the nerve impulse flow. J Neural Transm 64: 81–92
Andén N-E, Roos B-E, Werdinius B (1964) Effects of chlorpromazine, halo-peridol and reserpine on the levels of phenolic acids in rabbit corpus striatum. Life Sci 3: 149–158
Argiolas A, Melis MR, Fadda F, Serra G, Gessa GL (1982) Effect of dopamine agonists and antagonists on DOPA formation in the substantia nigra. J Neurochem 38: 75–79
Bartholini G (1976) Differential effect of neuroleptic drugs on dopamine turnover in the extrapyramidal and limbic system. J Pharm Pharmacol 28: 429–433
Boyce S, Kelly E, Davis A, Fleminger S, Jenner P, Marsden CD (1985) SCH 23390 may alter dopamine-mediated motor behaviour via striatal D-1 receptors. Biochem Pharmacol 34: 1665–1669
Brodie BB, Costa E, Dlabac A, Neff NH, Smookler HH (1966) Application of steady state kinetics to the estimation of synthesis rate and turnover time of tissue catecholamines. J Pharmacol Exp Ther 154: 493–498
Bunney BS, Walters JR, Roth RH, Aghajanian GK (1973) Dopaminergic neurones: effect of antipsychotic drugs and amphetamine on single cell activity. J Pharmacol Exp Ther 185: 560–571
Carlsson A, Lindqvist M (1963) Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) 20: 140–144
Carlsson A, Davis JN, Kehr W, Lindqvist M, Atack CV (1972) Simultaneous measurement of tyrosine and tryptophan hydroxylase activities in brainin vivo using an inhibitor of the aromatic amino acid decarboxylase. Naunyn Schmiedebergs Arch Pharmacol 275: 153–168
Corrodi H, Fuxe K, Hökfelt T (1967) The effect of neuroleptics on the activity of central catecholamine neurones. Life Sci 6: 767–774
Hallman H, Jonsson G (1984) Neurochemical studies on central dopamine neurons — regional characterization of dopamine turnover. Med Biol 62: 198–209
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
Jonsson G, Hallman H, Sundström E (1982) Effects of the noradrenaline neurotoxin DSP 4 on the postnatal development of central noradrenaline neurons in the rat. Neuroscience 7: 2895–2907
Kebabian JW, Calne DB (1979) Multiple receptors for dopamine. Nature 277: 93–96
Kebabian JW, Saavedra JM, Axelrod J (1977) A sensitive enzymatic radioisotopic assay for 3,4-dihydroxyphenylacetic acid. J Neurochem 28: 795–801
Magnusson O, Nilsson LB, Westerlund D (1980) Simultaneous determination of dopamine, DOPAC and homovanillic acid. Direct injection of supernatants from brain tissue homogenates in a liquid chromatography—electrochemical detection system. J Chromatogr 221: 237–247
Magnusson O, Fowler CJ, Köhler C, Ögren S-O (1986) Dopamine D 2 receptors and dopamine metabolism. Relationship between biochemical and behavioural effects of substituted benzamide drugs. Neuropharmacology 25: 187–197
Meller F, Friedhoff AJ, Friedman E (1980) Differential effects of acute and chronic haloperidol treatment on striatal and nigral 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Life Sci 26: 541–547
Nicolaou NM (1980) Acute and chronic effects of neuroleptics and acute effects of apomorphine and amphetamine on dopamine turnover in corpus striatum and substantia nigra of the rat brain. Eur J Pharmacol 64: 123–132
Nissbrandt H, Pileblad E, Carlsson A (1985) Evidence for dopamine release and metabolism beyond the control of nerve impulses and dopamine receptors in rat substantia nigra. J Pharm Pharmacol 37: 884–889
Ögren S-O, Hall H, Köhler C, Magnusson O, Lindbom L-O, Ängeby K, Florvall L (1984) Remoxipride, a new potential antipsychotic compound with selective antidopaminergic actions in the rat brain. Eur J Pharmacol 102: 459–474
Onali P, 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
Rollema H, Westerink BHC, Grol CJ (1976) Correlation between neuroleptic — induced suppression of stereotyped behaviour and HVA concentrations in rat brain. J Pharm Pharmacol 28: 321–323
Saller CF, Salama AI (1985) Dopamine receptor subtypes:in vivo biochemical evidence for functional interaction. Eur J Pharmacol 109: 297–300
Saller CF, Salama AI (1986) D-1 and D-2 dopamine receptor blockade: interactive effectsin vitro andin vivo. J Pharmacol Exp Ther 236: 714–720
Scatton B, Bischoff S, Dedek J, Korf J (1977) Regional effects of neuroleptics on dopamine metabolism and dopamine-sensitive adenylate cyclase activity. Eur J Pharmacol 44: 287–292
Tagliamonte A, De Montis G, Olianas M, Vargiu L, Corsini GU, Gessa GL (1975) Selective increase of brain dopamine synthesis by sulpiride. J Neurochem 24: 707–710
Waldmeier PC, Maitre L (1976) On the relevance of preferential increases of mesolimbic versus striatal dopamine turnover for the prediction of antipsychotic activity of psychotropic drugs. J Neurochem 27: 589–597
Westerink BHC (1979 a) The effects of drugs on dopamine biosynthesis and metabolism in the brain. In: Horn AS, Korf J, Westerink BHC (eds) The neurobiology of dopamine. Academic Press, London, pp 251–290
Westerink BHC (1979 b) Effects of drugs on the formation of 3-methoxytyramine, a dopamine metabolite, in the substantia nigra, striatum, nucleus accumbens and tuberculum olfactorium of the rat. J Pharm Pharmacol 31: 94–99
Westerink BHC, Korf J (1976) Regional brain levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid: concurrent fluorimetric measurement and influence of drugs. Eur J Pharmacol 38: 281–291
Zivkovic B, Guidotti A (1974) Changes of kinetic constant of striatal tyrosine hydroxylase elicited by neuroleptics that impair the function of dopamine receptors. Brain Res 79: 505–509
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Magnusson, O., Mohringe, B. & Fowler, C.J. Comparison of the effects of dopamine D 1 and D 2 receptor antagonists on rat striatal, limbic and nigral dopamine synthesis and utilisation. J. Neural Transmission 69, 163–177 (1987). https://doi.org/10.1007/BF01244339
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DOI: https://doi.org/10.1007/BF01244339