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General Pharmacology of Clozapine

Published online by Cambridge University Press:  06 August 2018

D. M. Coward
D. M. Coward*
Affiliation:
Sandoz Pharma Ltd, Clinical Research and Development, CH-4002 Basel, Switzerland
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Abstract

Clozapine shows neuroleptic-like inhibition of locomotor activity and conditioned avoidance responding in rodents, although tolerance develops on repeated treatment. EEG-based studies show strong arousal-inhibiting activity of clozapine as well as neuroleptic-like effects on both caudate spindle duration and rat sleep-waking patterns. Effects such as apomorphine blockade, catalepsy and strong increases of plasma prolactin levels are not seen, however, and chronic treatment does not lead to dopamine D2 receptor supersensitivity. Binding studies show clozapine's highest affinities to be for dopamine D4, 5-HT1c, 5-HT2, α1, muscarinic and histamine H1 receptors, but moderate affinity is also seen for many other receptor subtypes. Microdialysis studies indicate a preferential interaction with striatal D1 receptors, whereas autoradiographical studies indicate upregulation of D1 and downregulation of 5-HT2 receptors after chronic clozapine. Clarification of the mechanisms underlying clozapine's special attributes is often hampered by a failure to examine compounds which show a close chemical relationship to clozapine, but which produce extrapyramidal side-effects in man, such as clothiapine, loxapine and amoxapine.

Type
Research Article
Information
The British Journal of Psychiatry , Volume 160 , Issue S17: Clozapine - The Atypical Antipsychotic , May 1992 , pp. 5 - 11
Copyright
Copyright © The Royal College of Psychiatrists 

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References

Andersen, P. H. (1988) Comparison of the pharmacological characteristics of [3-H]SCH 23390 binding to dopamine receptors in vivo in mouse brain. European Journal of Pharmacology, 146, 113–120.Google Scholar
Andersen, P. H., Nielsen, E. B., Gronvald, F. C., et al (1986) Some atypical neuroleptics inhibit [3-H]SCH 23390 binding in vivo. European Journal of Pharmacology, 120, 143–144.Google Scholar
Angst, J., Bente, D., Berner, P., et al (1971) Das Klinische Wirkungsbild von Clozapin (Untersuchung mit dem AMP-system). Pharmacopsychiat, 4, 200–211.CrossRefGoogle Scholar
Blaha, C. D. & Lane, R. F. (1987) Chronic treatment with classical and atypical antipsychotic drugs differentially decreases dopamine release in striatum and nucleus accumbens in vivo. Neuroscience Letters, 78, 199–204.Google Scholar
Buerki, H.-R., Ruch, W. & Asper, H. (1974) Effect of single and repeated administration of clozapine on the metabolism of dopamine and noradrenaline in the brain of the rat. European Journal of Pharmacology, 27, 180–190.Google Scholar
Buerki, H.-R., Ruch, W. & Asper, H. (1975) Effects of clozapine, thioridazine, perlapine and haloperidol on the metabolism of the biogenic amines in the brain of the rat. Psychopharmacologia, 41, 27–33.CrossRefGoogle Scholar
Burt, D. R., Creese, I. & Snyder, S. H. (1976) Antischizophrenic drugs. Chronic treatment elevates dopamine receptor binding in brain. Science, 196, 326–328.Google Scholar
Canton, H., Verriele, L. & Colpaert, F. C. (1990) Binding of typical and atypical antipsychotics to 5-HT1C and 5-HT2 sites: clozapine potently interacts with 5-HT1C sites. European Journal of Pharmacology, 191, 93–96.Google Scholar
Chen, J., Paredes, W. & Gardner, E. L. (1991) Chronic treatment with clozapine selectively decreases basal dopamine release in nucleus accumbens but not in caudate-putamen as measured by in vivo brain microdialysis: further evidence for depolarization block. Neuroscience Letters, 122, 127–131.Google Scholar
Chiodo, L. A. & Bunney, B. S. (1983) Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons. Journal of Neuroscience, 3, 1607–1619.Google Scholar
Chiodo, L. A. & Bunney, B. S. (1985) Possible mechanisms by which repeated clozapine administration differentially affects the activity of two subpopulations of midbrain dopamine neurons. Journal of Neuroscience, 5, 2539–2544.CrossRefGoogle ScholarPubMed
Coward, D. M. (1982) Classical and non-classical neuroleptics induce supersensitivity of nigral GABA-ergic mechanisms in the rat. Psychopharmacology, 78, 180–184.CrossRefGoogle ScholarPubMed
Coward, D. M., Imperato, A., Urwyler, S., et al (1989) Biochemical and behavioural properties of clozapine. Psychopharmacology, 99, S6–S12.CrossRefGoogle ScholarPubMed
Coward, D. M., Dixon, A. K., Urwyler, S., et al (1990) Partial dopamine-agonistic and atypical neuroleptic properties of the amino-ergolines SDZ 208-911 and SDZ 208-912. Journal of Pharmacology and Experimental Therapeutics, 252, 279–285.Google ScholarPubMed
Farde, L., Wiesel, F.-A., Nordsröm, A.-L., et al (1989) D1 and D2 dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology, 99, S28–S31.Google Scholar
Frey, P., Fuxe, K., Eneroth, P., et al (1986) Effects of acute and long-term treatment with neuroleptics on regional telencephalic neurotensin levels in the male rat. Neurochemistry International, 8, 429–434.Google Scholar
Frey, P., Lis, M. & Coward, D. M. (1988) Neurotensin concentrations in rat striatum and nucleus accumbens: further studies of their regulation. Neurochemistry International, 12, 33–38.CrossRefGoogle ScholarPubMed
Gale, K. (1980) Chronic blockade of dopamine receptors by antischizophrenic drugs enhances GABA binding in substantia nigra. Nature, 283, 569–570.CrossRefGoogle ScholarPubMed
Gallager, D. W. & Aghajanian, G. K. (1976) Effect of antipsychotic drugs on the firing of dorsal raphe cells. I. Role of adrenergic system. European Journal of Pharmacology, 39, 341–355.CrossRefGoogle ScholarPubMed
Govoni, J. S., Hong, H.-Y. T. & Costa, E. (1980) Increase of neurotensin content elicited by neuroleptics in nucleus accumbens. Journal of Pharmacology and Experimental Therapeutics, 215, 413–417.Google Scholar
Gudelsky, G. A., Nash, J. F., Berry, S. A., et al (1989) Basic biology of clozapine: electrophysiological and neuroendocrinological studies. Psychopharmacology, 99, S13–S17.Google Scholar
Gunne, L.-M. & Haggstrom, J.-E. (1983) Reduction of nigral glutamic acid decarboxylase in rats with neuroleptic-induced dyskinesia. Psychopharmacology, 81, 191–194.CrossRefGoogle Scholar
Gunne, L.-M. & Haggstrom, J.-E., & Sjoquist, B. (1984) Association with persistent neuroleptic-induced dyskinesia of regional changes in brain GABA synthesis. Nature, 309, 347–349.Google Scholar
Hartvig, P., Eckernas, S. A., Lindström, L., et al (1986) Receptor binding of N-(methyl-11-C)clozapine in the brain of rhesus monkey studied by positron emission tomography. Psychopharmacology, 89, 248–252.Google Scholar
Hess, E. J., Norman, A. B. & Creese, I. (1988) Chronic treatment with dopamine receptor antagonists: behavioural and pharmacological effects on D1 and D2 dopamine receptors. Journal of Neuroscience, 8, 2361–2370.Google Scholar
Hoyer, D., Gozlan, H., Bolanos, F., et al (1989) Interaction of psychotropic drugs with central 5-HT3 recognition sites: fact or artifact? European Journal of Pharmacology, 171, 137–139.CrossRefGoogle ScholarPubMed
Ichikawa, J. & Meltzer, H. Y. (1990) The effect of chronic clozapine and haloperidol on basal dopamine release and metabolism in rat striatum and nucleus accumbens studied by in vivo microdialysis. European Journal of Pharmacology, 176, 371–374.Google Scholar
Imperato, A. & Angelucci, L. (1988) Effects of the atypical neuroleptics clozapine and fluperlapine on the in vivo dopamine release in the dorsal striatum and in the prefrontal cortex. Psychopharmacology, 96, 79.Google Scholar
Kane, J., Honigfeld, G., Singer, J., et al (1988) Clozapine for the treatment-resistant schizophrenic. Archives of General Psychiatry, 45, 789–796.Google Scholar
Krupp, P. & Barnes, P. (1989) Leponex-associated granulocytopenia: a review of the situation. Psychopharmacology, 99, S118–S121.Google Scholar
LaHoste, G. J., O'Dell, S. J., Widmark, C. B., et al (1991) Differential changes in dopamine and serotonin receptors induced by clozapine and haloperidol. In Advances in Neuropsychiatry and Psychopharmacology (eds C. A. Tamminga & S. C. Schulz), Vol. 1, pp. 351–361. New York: Raven Press.Google Scholar
Lamberts, S. W. J., van Koetsveld, P. M. & Hofland, L. J. (1990) The effect of clozapine on prolactin secretion at the level of the lactotroph. Life Sciences, 46, 1013–1019.CrossRefGoogle ScholarPubMed
Lee, T. & Tang, S. W. (1984) Loxapine and clozapine decrease serotonin (S2) but do not elevate dopamine (D2) receptor numbers in the rat brain. Psychiatry Research, 12, 277–285.Google Scholar
Leysen, J. E., Gommeren, W., Janssen, P. F. M., et al (1988) Receptor interactions of dopamine and serotonin antagonists: binding in vitro and in vivo and receptor regulation. In Psychopharmacology: Current Trends (eds D. E. Casey & A. V. Christensen), pp. 12–26. Berlin: Springer.Google Scholar
Mao, C. C., Cheney, D. L., Marco, E., et al (1977) Turnover times of gamma-butyric acid and acetylcholine in nucleus caudatus, nucleus accumbens, globus pallidus and substantia nigra: effects of repeated administration of haloperidol. Brain Research, 132, 375–379.CrossRefGoogle Scholar
Marco, E., Mao, C. C., Cheney, D. L., et al (1976) The effects of antipsychotics on the turnover rate of GABA and acetylcholine in rat brain nuclei. Nature, 264, 363–365.Google Scholar
Matsubara, S. & Meltzer, H. Y. (1989) Effect of typical and atypical antipsychotic drugs on 5-HT2 receptor density in rat cerebral cortex. Life Sciences, 45, 1397–1406.CrossRefGoogle ScholarPubMed
Meltzer, H. Y., Daniels, S. & Fang, V. S. (1975) Clozapine increases rat serum prolactin levels. Life Sciences, 17, 339–342.CrossRefGoogle ScholarPubMed
Meltzer, H. Y., Matsubara, S. & Lee, J.-C. (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1, D2 and serotonin-2 pKi values. Journal of Pharmacology and Experimental Therapeutics, 251, 238–246.Google Scholar
Menon, M. K., Gordon, L. I. & Fitten, J. (1988) Interaction between clozapine and a lipophilic alpha-1 adrenergic agonist. Life Sciences, 43, 1791–1804.Google Scholar
Meyer, D. K. & Krauss, J. (1983) Dopamine modulates chole-cystokinin release in neostriatum. Nature, 301, 338–340.Google Scholar
Murray, A. M. & Waddington, J. L. (1990) The interaction of clozapine with dopamine D1 versus dopamine D2 receptor-mediated function: behavioural indices. European Journal of Pharmacology, 186, 79–86.CrossRefGoogle ScholarPubMed
Rupniak, N. M. J., Hall, M. D., Mann, S., et al (1985) Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D2 receptor function in the rat. Biochemical Pharmacology, 34, 2755–2763.Google Scholar
Sanger, D. J. (1985) The effects of clozapine on shuttle-box avoidance responding in rats: comparisons with haloperidol and chlordiazepoxide. Pharmacology, Biochemistry and Behavior, 23, 231–236.Google Scholar
Sayers, A. C., Buerki, H.-R., Ruch, W., et al (1975) Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, loxapine and chlorpromazine. Psychopharmacologia, 41, 97–104.CrossRefGoogle Scholar
Sayers, A. C., Buerki, H.-R., Ruch, W., et al (1976) Anticholinergic properties of antipsychotic drugs and their relation to extrapyramidal side-effects. Psychopharmacology, 51, 15–22.Google Scholar
Schmutz, J. (1975) Neuroleptic piperazinyl-dibenzo-azepines. Arzneimittel-Forschung, 25, 712–720.Google ScholarPubMed
Seeman, P. (1980) Brain dopamine receptors. Pharmacological Reviews, 32, 229–313.Google Scholar
Sokoloff, P., Giros, B., Martres, M.-P., et al (1990) Molecular cloning and characterisation of a novel type of dopamine receptor (D-3) as a target for neuroleptics. Nature, 347, 146–151.Google Scholar
Stille, G., Lauener, H. & Eichenberger, E. (1971) The pharmacology of 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e] [1,4]diazepine (Clozapine). Il Pharmaco, 26, 603–625.Google Scholar
Stille, G. & Hippius, H. (1971) Kritische Stellungnahme zum Begriff der Neuroleptika (und von pharmakologischen und klinischen Befunden mit Clozapin). Pharmacopsychiat, 4, 182–191.Google Scholar
Sunahara, R. K., Guan, H.-C., O'Dowd, B. F., et al (1991) Cloning of the gene for a human D5 receptor with higher affinity for dopamine than D1 . Nature, 350, 614–619.CrossRefGoogle ScholarPubMed
Sunderland, T., Orsulak, P. J. & Cohen, B. M. (1983) Amoxapine and neuroleptic side effects: a case report. American Journal of Psychiatry, 140, 1233–1235.Google ScholarPubMed
Van Tol, H. H. M., Riva, M., Civelli, O., et al (1990) Lack of effect of chronic dopamine receptor blockade on D2 dopamine receptor mRNA level. Neuroscience Letters, 111, 303–308.Google Scholar
Van Tol, H. H. M., Bunzow, J. R., Guan, H.-C., et al (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature, 350, 610–614.Google Scholar
White, T. G. (1979) The pharmacology and neurochemistry of 106-689. Data on file, Sandoz Ltd, Basle.Google Scholar
White, F. J. & Wang, R. Y. (1983) Comparison of the effects of chronic haloperidol treatment on A9 and A10 dopamine neurons in the rat. Life Sciences, 32, 983–993.Google Scholar
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