Hostname: page-component-77f85d65b8-t6st2 Total loading time: 0 Render date: 2026-04-15T04:21:54.417Z Has data issue: false hasContentIssue false
  • English
  • Français

The Importance of Serotonin-Dopamine Interactions in the Action of Clozapine

Published online by Cambridge University Press:  06 August 2018

Herbert Y. Meltzer
Herbert Y. Meltzer*
Affiliation:
University Hospitals of Cleveland, Hanna Pavilion, Room B-68, 2040 Abingdon Road, Cleveland, OH 44106-5000, USA
Get access Rights & Permissions [Opens in a new window]

Abstract

Clozapine has an affinity for the dopamine (DA) D2 receptor which is relatively weak but is in line with its average clinical dose when compared with typical neuroleptic drugs. A few atypical antipsychotic drugs may have high absolute affinities for the D2 receptor, but most are weak D2 blockers. The atypical antipsychotic drugs also differ from the typical antipsychotic drugs by a relatively high affinity for the serotonin (5-HT2) receptor. This is evident on both in vitro and in vivo binding to cortical 5-HT2 receptors. The atypical antipsychotics are best distinguished from the typical antipsychotics on the basis of the relationship between strong 5-HT2 and weak D2 affinities. High D1 receptor binding is not characteristic of the group of atypical drugs. A new group of putative atypical antipsychotic drugs with high affinities for 5-HT2 compared to D2 receptors is under study.

Information

Type
Research Article
Information
The British Journal of Psychiatry , Volume 160 , Issue S17: Clozapine - The Atypical Antipsychotic , May 1992 , pp. 22 - 29
Copyright
Copyright © The Royal College of Psychiatrists 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

Altar, C. A., Wasley, A. M., Neale, R. F., et al (1986) Typical and atypical antipsychotic occupancy of D2 and S2 receptors: an autoradiographic analysis in rat brain. Brain Research Bulletin, 16, 517–525.Google Scholar
Andersen, P. H., Nielsen, E. B., Gr$oSnveld, C., et al (1986) Some atypical neuroleptics inhibit [3H]SCH 23390 binding in vivo. European Journal of Pharmacology, 120, 143–144.Google Scholar
Balsara, J. J., Jadhav, J. H. & Chandorkar, A. G. (1979) Effect of drugs influencing central serotonergic mechanisms on haloperidol-induced catalepsy. Psychopharmacology, 22, 67–69.Google Scholar
Bersani, G., Grispini, A., Marini, S., et al (1986) Neuroleptic-induced extrapyramidal side effects: clinical perspectives with ritanserin (R35667), a new selective 5-HT2 receptor blocking agent. Current Therapeutic Research, 40, 492–499.Google Scholar
Blandina, P., Goldfarb, J., Craddock-Royal, B., et al (1989) Release of endogenous dopamine by stimulation of 5-hydroxytryptamine3 receptors in rat striatum. Journal of Pharmacology and Experimental Therapeutics, 351, 803–809.Google Scholar
Brougham, L. R., Conway, P. G. & Ellis, D. B. (1991) Effect of ritanserin on the interaction of amfonelic acid and neuroleptic-induced striatal dopamine metabolism. Neuropharmacology, 30, 1137–1140.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
Costall, B., Fortune, D. H., Naylor, R. J., et al (1975) Serotonergic involvement with neuroleptic catalepsy. Neuropharmacology, 14, 859–868.CrossRefGoogle ScholarPubMed
Creese, I., Burt, D. R. & Snyder, S. H. (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of anti-schizophrenic drugs. Science, 192, 481–483.Google Scholar
De Belleroche, J. S. & Bradford, H. F. (1980) Presynaptic control of the synthesis and release of dopamine from striatal synaptosomes: a comparison between the effects of 5-hydroxytryptamine, acetylcholine, and glutamate. Journal of Neurochemistry, 35, 1227–1234.Google Scholar
De Belleroche, J. S. & Gardiner, I. M. (1982) Contrasting effects of 5-hydroxytryptamine on the release of dopamine and acetylcholine in the nucleus accumbens of rat. Journal of Neural Transmission, 55, 227–242.Google Scholar
Deutch, A. Y., Moghaddam, B., Innis, R. B., et al (1991) Mechanisms of action of atypical antipsychotic drugs. Implications for novel therapeutic strategies for schizophrenia. Schizophrenia Research, 4, 121–156.Google Scholar
Dray, A., Gonye, T. J., Oakley, N. R., et al (1976) Evidence for the existence of a raphe projection to the substantia nigra in rat. Brain Research, 113, 45–57.CrossRefGoogle Scholar
Ellenbroek, B. A., Peeters, B. W., Honig, W. M., et al (1987) The paw test: a behavioural paradigm for differentiating between classical and atypical neuroleptic drugs. Psychopharmacology, 93, 343–348.Google Scholar
Ellenbroek, B. A., Artz, M. T. & Coles, A. R. (1991) The involvement of dopamine D1 and D2 receptor in the effects of the classical neuroleptic haloperidol and the atypical neuroleptic clozapine. European Journal of Pharmacology, 196, 103–108.Google Scholar
Farde, L., Wiesel, F. A., Nordstrom, A.-L., et al (1989) D1-and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology, 99, (suppl.), S28–S31.Google Scholar
Fink, H., Mogenstern, R. & Oelsner, W. (1984) Clozapine - a serotonin antagonist? Pharmacology, Biochemistry and Behavior, 20, 513–517.Google Scholar
Fjalland, B. (1979) Neuroleptic influence on hyperthermia induced by 5-hydroxytryptophan and p-methoxy-amphetamine in MAOI-pretreated rabbits. Psychopharmacology, 63, 113–117.Google Scholar
Gerlach, J., Behnke, K., Heltberg, J., et al (1985) Sulpiride and haloperidol in schizophrenia: a double-blind cross-over study of therapeutic effect, side effects and plasma concentrations. British Journal of Psychiatry, 147, 283–288.Google Scholar
Hervé, D., Simon, H., Blanc, G., et al (1981) Opposite changes in dopamine utilization in the nucleus accumbens and the frontal cortex after electrolytic lesion of the median raphe in the rat. Brain Research, 216, 422–428.Google Scholar
Ichikawa, J. & Meltzer, H. Y. (1990) Differential effects of repeated treatment with haloperidol and clozapine on dopamine release and metabolism in the striatum and nucleus accumbens. Journal of Pharmacology and Experimental Therapeutics, 256, 348–357.Google Scholar
Imperato, A. & Angelucci, L. (1989) The effect of clozapine and fluperlapine on the in vivo release and metabolism of dopamine in the striatum and in the frontal cortex of freely-moving rats. Psychopharmacology Bulletin, 25, 383–389.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
Kohler, C., Hall, H., Magnusson, O., et al (1990) Biochemical pharmacology of the atypical neuroleptic remoxipride. Acta Psychiatrica Scandinavica, 82 (suppl. 358), 27–36.CrossRefGoogle Scholar
Korsgaard, S., Gerlach, J. & Christensson, E. (1985) Behavioral aspects of serotonin-dopamine interaction in the monkey. European Journal of Pharmacology, 118, 245–252.Google Scholar
Kostowski, W., Gumulka, W. & Czlonkowski, A. (1972) Reduced cataleptogenic effects of some neuroleptics in rats with lesioned midbrain raphe and treated with p-chlorophenylalanine. Brain Research, 48, 443–446.Google Scholar
Lai, H., Carino, M. A. & Horita, A. (1980) Antiserotonin properties of neuroleptic drugs. In Psychopharmacology and Biochemistry of Neurotransmitter Receptors (eds H.I. Yamamura, R. W. Olsen & E. Usdin), pp. 347–353. Amsterdam: Elsevier Scientific.Google Scholar
Lappalainen, J., Hietala, J., Koulou, M., et al (1990) Neurochemical effects of chronic co-administration of ritanserin and haloperidol: comparison with clozapine effects. European Journal of Pharmacology, 190, 403–407.Google Scholar
Lee, M. A., Nash, J. F., Barnes, M., et al (1991) Inhibitory effect of ritanserin on the 5-hydroxytryptophan-mediated cortisol, ACTH and prolactin secretion in humans. Psychopharmacology, 103, 258–264.Google Scholar
Lewander, T., Westerbeigh, S.-E. & Morrison, D. (1990) A combined analysis for comparative double-blind multicentre trial programme. Acta Psychiatrica Scandinavica, 82 (suppl. 358), 92–98.CrossRefGoogle Scholar
Maj, J., Sowinska, H., Boran, L., et al (1974) The central action of clozapine. Polish Journal of Pharmacology and Pharmacy, 26, 425–435.Google Scholar
Maj, J., Sarnek, J., Klimek, V., et al (1976) On the anticataleptic action of cyproheptadine. Pharmacology, Biochemistry and Behavior, 5, 201–205.Google Scholar
Maj, J., Baran, L., Bigaiska, K., et al (1978) The influence of neuroleptics on the behavioral effect of 5-hydroxytryptophan. Polish Journal of Pharmacology, 30, 431–440.Google Scholar
Mann, J. J., Bartles, M., Bauer, H., et al (1984) Amisulpride - an open clinical study of a new benzamide in schizophrenic patients. Pharmacopsychiatry, 17, 111–115.CrossRefGoogle ScholarPubMed
Mansour, A., Meador-Woodruff, J., Burke, S., et al (1991) Differential distribution of D2 and D4 dopamine receptor mRNAs in the rat brain: an in situ hybridization study. Society of Neuroscience Abstracts, 17, 599.Google Scholar
Meador-Woodruff, J., Mansour, A., Work, C., et al (1991) Localization of D4 and D5 dopamine receptor mRNAs in the human brain. Society of Neuroscience Abstracts, 17, 599.Google Scholar
Meltzer, H. Y. (1988) Clozapine: clinical advantages and biological mechanisms. In Schizophrenia: A Scientific Focus, International Conference on Schizophrenia (eds C. Schulz & C. Tamminga), pp. 302–309. New York: Oxford Press.Google Scholar
Meltzer, H. Y. (1990) Clozapine: mechanism of action in relation to its clinical advantages. In Recent Advances in Schizophrenia (eds A. Kales, G. N. Stefanos & J. A. Talbott), pp. 237–246. Heidelberg, New York & Tokyo: Springer-Verlag.Google Scholar
Meltzer, H. Y. (1991a) The mechanism of action of novel antipsychotic drugs. Schizophrenia Bulletin, 17, 263–287.Google Scholar
Meltzer, H. Y., Goode, D. J., Schyve, P. M., et al (1979a) Effect of clozapine on human serum prolactin levels. American Journal of Psychiatry, 136, 1550–1555.Google Scholar
Meltzer, H. Y., Young, M., Metz, J., et al (1979b) Extrapyramidal side effects and increased serum prolactin following fluoxetine, a new antidepressant. Journal of Neural Transmission, 45, 165–175.Google Scholar
Meltzer, H. Y., Bastani, B., Kwon, K. Y., et al (1989a) A prospective study of clozapine in treatment-resistant patients. 1. Preliminary report. Psychopharmacology, 99, S68–S72.Google Scholar
Meltzer, H. Y., Matsubara, S. & Lee, J.-C. (1989b) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1, D2 and serotonin2 pKsb values. Journal of Pharmacology and Experimental Therapeutics, 251, 238–246.Google Scholar
Meltzer, H. Y., Burnett, S., Bastani, B., et al (1990a) Effect of six months of clozapine treatment on the quality of life of chronic schizophrenic patients. Hospital and Community Psychiatry, 41, 892–897.Google Scholar
Meltzer, H. Y., Zhang, Y. & Stockmeier, C. (1990b) Effect of typical and atypical antipsychotic drugs (APD) on frontal cortical (FC), serotonin2 (5-HT2) and striatal (STR) dopamine2 (DA2) binding in vivo. Neuroscience Abstracts, 16, 586.Google Scholar
Meltzer, H. Y. & Nash, J. F. (1992) The effects of antipsychotic drugs on serotonin receptors. Pharmacological Reviews (in press).Google Scholar
Mesotten, F., Suy, E., Pietquin, M., et al (1989) Therapeutic effect and safety of increasing doses of risperidone (R 64766) in psychotic patients. Psychopharmacology, 99, 445–449.Google Scholar
Miller, R. J. & Hiley, C. D. (1976) Anti-dopaminergic and anti-muscarinic effects of dibenzodiazepines. Relationship to drug-induced parkinsonism. Naunyn-Schmiedeberg's Archives of Pharmacology, 292, 289–293.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.Google Scholar
Nash, J. F. (1990) Ketanserin pretreatment blocks MDMA-induced dopamine release in the striatum as measured by in vivo microdialysis. Life Sciences, 47, 2401–2408.Google Scholar
Nash, J. F., Meltzer, H. Y. & Gudelsky, G. A. (1988) Antagonism of serotonin receptor mediated neuroendocrine and temperature responses by atypical neuroleptics in the rat. European Journal of Pharmacology, 151, 463–469.Google Scholar
Nash, J. F., Meltzer, H. Y. & Gudelsky, G. A. (1990) Effect of 3,4-methylenedioxy-methamphetamine on 3,4-dihydroxyphenylalanine accumulation in the striatum and nucleus accumbens. Journal of Neurochemistry, 54, 1062–1067.Google Scholar
North, R. A. & Uchimura, N. (1989) 5-Hydroxytryptamine acts at 5-HT2 receptors to decrease potassium conductance in rat nucleus accumbens neurons. Journal of Physiology, 417, 1–12.CrossRefGoogle Scholar
Rao, T. S., Contreras, P. C., Cler, J. A., et al (1991) Clozapine attenuates N-methyl-D-aspartate receptor complex-mediated responses in vivo: tentative evidence for a functional modulation by a noradrenergic mechanism. Neuropharmacology, 30, 557–565.Google Scholar
Rasmussen, K. & Aghajanian, G. K. (1988) Potency of antipsychotics in reversing the effects of a hallucinogenic drug on locus coeruleus neurons correlates with 5-HT2 binding affinity. Neuropsychopharmacology, 1, 101–107.Google Scholar
Rivest, R. & Marsden, C. A. (1991) Muscarinic antagonists attenuate the increase in accumbens and striatum dopamine metabolism produced by clozapine but not by haloperidol. British Journal of Pharmacology, 104, 234–238.Google Scholar
Roth, B. K., Giaranello, R. D. & Meltzer, H. Y. (1992) Binding of typical and atypical antipsychotic agents to transiently expressed 5-HT1C receptors. Journal of Pharmacology and Experimental Therapeutics (in press).Google Scholar
Scholz, E. & Dichgans, J. (1985) Treatment of drug-induced exogenous psychosis in Parkinsonism with clozapine and fluperlapine. European Archives of Psychiatric Neurological Science, 235, 60–64.Google Scholar
Seeman, P., Lee, T., Chau-Wong, M., et al (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature, 261, 717–718.Google Scholar
Soubrié, P., Reisine, T. D. & Glowinski, J. (1984) Functional aspects of serotonin transmission in the basal ganglia: a review and an in vivo approach using the push-pull cannula technique. Neuroscience, 131, 605–625.Google Scholar
Sulpizio, A., Fowler, P. J. & Macko, E. (1978) Antagonism of fenfluramine-induced hyperthermia: a measure of central serotonin inhibition. Life Sciences, 22, 1439.Google Scholar
Ugedo, L., Grenhoff, J. & Svensson, T. H. (1989) Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition. Psychopharmacology, 98 45–50.CrossRefGoogle ScholarPubMed
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
Watling, K. J., Beer, M. S. & Stanton, J. S. (1989) Effect of clozapine and other neuroleptics on binding of [3H]-QICS 205-930 to central 5-HT3 recognition sites. British Journal of Pharmacology, 98, 813P.Google Scholar

This journal is not currently accepting new eletters.

eLetters

No eLetters have been published for this article.