Abstract
The effect of various antipsychotic drugs on the blockade of dopaminergic receptors in striatum and limbic forebrain was examined by establishing dose-response curves for the increase in HVA and for the antagonism of d-amphetamine-induced rotation in rats with unilateral lesions of the substantia nigra. A good quantitative correlation was found between dopaminergic blockade in the striatum as reflected by the ED100 for striatal HVA increase and the ED50 for rotational antagonism and the occurrence of extrapyramidal side effects in man. The ED100 for the increase in HVA in the limbic forebrain showed the same rank order of potency as those in the striatum: Haloperidol > pimozide > chlorpromazine > thioridazine > clozapine. The results thus demonstrate a very good correlation between the degree of dopaminergic blockade and the increase of extrapyramidal side effects in man, but suggest the possibility of a dissociation between dopaminergic blockade and antipsychotic activity.
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Ackenheil, M., Beckmann, H., Greil, W., Hoffmann, R., Markianos, E., Raese, J.: Antipsychotic efficacy of clozapine in correlation to changes in catecholamine metabolism in man. Advanc. Biochem. Psychopharmacol. 9, 647–658 (1974)
Andén, N. E.: Dopamine turnover in the corpus striatum and the limbic system after treatment with neuroleptic and antiacetylcholine drugs. J. Pharmac. Pharmacol. 9, 905–906 (1972)
Andén, N. E., Stock, G.: Effect of clozapine on the turnover of dopamine in the corpus striatum and in the limbic system. J. Pharmac. Pharmacol. 25, 346–348 (1973)
Andén, N. E., Roos, B. E., Werdinius, B.: The occurrence of homovanillic acid in the brain and cerebral fluid and its determination by a fluorometric method. Life Sci. 2, 448–458 (1963)
Andén, N. E., Roos, B. E., Werdinius, B.: Effect of chlorpromazine, haloperidol and reserpine on the levels of phenolic acids in rabbit corpus striatum. Life Sci. 3, 149–158 (1964)
Andén, N. E., Butcher, Sg., Corrodi, H., Fuxe, K., Ungerstedt, U.: Receptor activity and turnover of dopamine and noradrenaline after neuroleptics. Europ. J. Pharmacol. 11, 303–314 (1970)
Angst, J., Bente, D., Berner, P., Heimann, H., Helmchen, H., Hippius, H.: Das klinische Wirkungsbild von Clozapine. Pharmakopsychiat. Neuropsychopharmak. 4, 209–211 (1971a)
Angst, J., Jaewicke, U., Padrutt, A., Scharfetter, Ch.: Ergebnisse eines Doppelblindversuches von HF-1854 [8-chlor-11-(methyl-1-piperazinyl)-5H-dibenzo b, e 1,4-diazepin] im Vergleich zu levomepromazine. Pharmakopsychiat. Neuropsychopharmak. 4, 192–200 (1971b)
Bartholini G., Haefely, W., Jalfre, M., Pletscher, A.: Effects of clozapine on cerebral catecholaminergic neurone systems. Brit. J. Pharmacol. 46, 736–740 (1972)
Berzewski, H., Helmchen, H., Hippius, H., Hoffman, H., Karnowski, S.: Das klinische Wirkungsspektrum eines neuen Dibenzodiazepin Derivates. Arzneimittel-Forsch. 19, 495–496 (1969)
Blumberg, J. B., Taylor, R. E., Sulser, F.: Blockade by pimozide of a norepinephrine-sensitive adenylate cyclase in the limbic forebrain: Possible role of limbic noradrenergic mechanisms in the mode of action of antipsychotics. J. Pharm. Pharmacol. 27, 125–128 (1975)
Bowers, M. B., Roth, R. H.: Interaction of atropine-like drugs with dopamine-containing neurones in rat brain. Brit. J. Pharmacol. 44, 301–306 (1972)
Bunney, B. S., Walters, J. R., Roth, R. H., Aghajanian, G. K.: Dopaminergic neurons: Effect of antipsychotic drugs and amphetamine on single cell activity. J. Pharmacol. exp. Ther. 185, 560–571 (1973)
Bürki, H. R., Ruch, W., Asper, H., Baggiolini, M., Stille, G.: Pharmakologische und neurochemische Wirkungen von Clozapin: Neue Gesichtspunkte in der medikamentösen Behandlung der Schizophrenie. Schweiz, med. Wschr. 103, 1716–1724 (1973)
Bürki, H. R., Ruch, W., Asper, H., Baggiolini, M., Stille, G.: Effect of single and repeated administration of clozapine on the metabolism of dopamine and noradrenaline in the brain of rat. Europ. J. Pharmacol. 27, 180–190 (1974)
Carlsson, A., Lindqvist, M.: Effect of chlorpromazine and haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta pharmacol. (Kbh.) 20, 140–144 (1963)
Clement-Cormier, Y., Kebabian, J. W., Petzold, G. L., Greengard, P.: Dopamine sensitive adenylate cyclase in mammalian brain: A possible site of action of antipsychotic drugs. Proc. nat. Acad. Sci. (Wash.) 71, 1113–1117 (1974)
De-Maio, D.: Clozapine, a novel major tranquilizer. Arznei-mittel-Forsch. 22, 919–923 (1972)
Ekblom, B., Haggstrom, J. E.: Clozapine (Leponex) compared with chlorpromazine: A double-blind evaluation of pharmacological and clinical properties. Curr. Ther. Res. 16, 945–957 (1974)
Horn, A. S., Cuello, A. C., Miller, R. J.: Dopamine in the mesolimbic system of the rat brain: Endogenous levels and the effect of drugs on the uptake mechanism and the stimulation of adenylate cyclase activity. J. Neurochem. 22, 265–270 (1974)
Kebabian, J. W., Petzold, G. L., Greengard, P.: Dopaminesensitive adenylate cyclase in caudate nucleus of rat brain and its similarity to the dopamine receptor. Proc. nat. Acad. Sci. (Wash.) 69, 2145–2149 (1972)
Matz, R., Rick, W., Oh, D., Thompson, H., Gershon, S.: Clozapine, a potential antipsychotic agent without extrapyramidal manifestations. Curr. Ther. Res. 16, 687–695 (1974)
Miller, R. J., Hiley, C. R.: Antimuscarinic properties of neuroleptics and drug-induced Parkinsonism. Nature (Lond.) 248, 596–597 (1974)
O'Keefe, R., Sharman, D. F., Vogt, M.: Effect of drugs used in psychoses on cerebral dopamine metabolism. Brit. J. Pharmacol. 38, 287–304 (1970)
Pletscher, A., Gey, K. F., Burkard, W. P.: Effect of neuroleptics on the cerebral metabolism of catecholamines. In: Toxicity and side effects of psychotropic drugs, pp. 98–106, Excerpta Medica Int. Congress Series 145 (1967)
Stille, G., Lauener, H., Eichenberger, E.: The pharmacology of 8-chloro-11-(4-methyl-l-piperazinyl-5H-dibenzo b, e 1,4-diazepine) (clozapine). Farmaco 26, 603–625 (1971)
Snyder, S., Greenberg, D., Yamamura, H. I.: Antischizophrenic drugs and brain cholinergic receptors. Arch. gen. Psychiat. 31, 58–61 (1974)
Sulser, F., Stawarz, R. J., Blumberg, J. B.: The limbic forebrain: The role of catecholamines and cyclic AMP in the mode of action of antipsychotics. In: Proc. IX. CINP Congress, Paris, France (in press, 1975)
Ungerstedt, U.: Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behavior. Acta physiol. scand. 82 (Suppl. 367), 49–68 (1971)
Van Rossum, J. M., Janssen, P. A. J., Boissier, J. R., Julou, L., Loew, D. M., Moller-Nielsen, I., Munkvad, I., Randrup, A., Stille, G.: The neuroleptics. In: Modern problems of pharmacopsychiatry, D. P. Bobon, P. A. J. Janssen, and J. Bobon, eds., pp. 23–32. Basel: Karger 1971
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Stawarz, R.J., Hill, H., Robinson, S.E. et al. On the significance of the increase in homovanillic acid (HVA) caused by antipsychotic drugs in corpus striatum and limbic forebrain. Psychopharmacologia 43, 125–130 (1975). https://doi.org/10.1007/BF00421014
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DOI: https://doi.org/10.1007/BF00421014