Skip to main content Accessibility help
×
Home

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

  • Herbert Y. Meltzer (a1)

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.

Copyright

References

Hide All
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, 517525.
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, 143144.
Balsara, J. J., Jadhav, J. H. & Chandorkar, A. G. (1979) Effect of drugs influencing central serotonergic mechanisms on haloperidol-induced catalepsy. Psychopharmacology, 22, 6769.
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, 492499.
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, 803809.
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, 11371140.
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, 9396.
Costall, B., Fortune, D. H., Naylor, R. J., et al (1975) Serotonergic involvement with neuroleptic catalepsy. Neuropharmacology, 14, 859868.
Creese, I., Burt, D. R. & Snyder, S. H. (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of anti-schizophrenic drugs. Science, 192, 481483.
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, 12271234.
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, 227242.
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, 121156.
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, 4557.
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, 343348.
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, 103108.
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.), S28S31.
Fink, H., Mogenstern, R. & Oelsner, W. (1984) Clozapine - a serotonin antagonist? Pharmacology, Biochemistry and Behavior, 20, 513517.
Fjalland, B. (1979) Neuroleptic influence on hyperthermia induced by 5-hydroxytryptophan and p-methoxy-amphetamine in MAOI-pretreated rabbits. Psychopharmacology, 63, 113117.
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, 283288.
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, 422428.
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, 348357.
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, 383389.
Kane, J., Honigfeld, G., Singer, J., et al (1988) Clozapine for the treatment-resistant schizophrenic. Archives of General Psychiatry, 45, 789796.
Kohler, C., Hall, H., Magnusson, O., et al (1990) Biochemical pharmacology of the atypical neuroleptic remoxipride. Acta Psychiatrica Scandinavica, 82 (suppl. 358), 2736.
Korsgaard, S., Gerlach, J. & Christensson, E. (1985) Behavioral aspects of serotonin-dopamine interaction in the monkey. European Journal of Pharmacology, 118, 245252.
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, 443446.
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. 347353. Amsterdam: Elsevier Scientific.
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, 403407.
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, 258264.
Lewander, T., Westerbeigh, S.-E. & Morrison, D. (1990) A combined analysis for comparative double-blind multicentre trial programme. Acta Psychiatrica Scandinavica, 82 (suppl. 358), 9298.
Maj, J., Sowinska, H., Boran, L., et al (1974) The central action of clozapine. Polish Journal of Pharmacology and Pharmacy, 26, 425435.
Maj, J., Sarnek, J., Klimek, V., et al (1976) On the anticataleptic action of cyproheptadine. Pharmacology, Biochemistry and Behavior, 5, 201205.
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, 431440.
Mann, J. J., Bartles, M., Bauer, H., et al (1984) Amisulpride - an open clinical study of a new benzamide in schizophrenic patients. Pharmacopsychiatry, 17, 111115.
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.
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.
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. 302309. New York: Oxford Press.
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. 237246. Heidelberg, New York & Tokyo: Springer-Verlag.
Meltzer, H. Y. (1991a) The mechanism of action of novel antipsychotic drugs. Schizophrenia Bulletin, 17, 263287.
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, 15501555.
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, 165175.
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, S68S72.
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, 238246.
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, 892897.
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.
Meltzer, H. Y. & Nash, J. F. (1992) The effects of antipsychotic drugs on serotonin receptors. Pharmacological Reviews (in press).
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, 445449.
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, 289293.
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, 7986.
Nash, J. F. (1990) Ketanserin pretreatment blocks MDMA-induced dopamine release in the striatum as measured by in vivo microdialysis. Life Sciences, 47, 24012408.
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, 463469.
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, 10621067.
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, 112.
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, 557565.
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, 101107.
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, 234238.
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).
Scholz, E. & Dichgans, J. (1985) Treatment of drug-induced exogenous psychosis in Parkinsonism with clozapine and fluperlapine. European Archives of Psychiatric Neurological Science, 235, 6064.
Seeman, P., Lee, T., Chau-Wong, M., et al (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature, 261, 717718.
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, 605625.
Sulpizio, A., Fowler, P. J. & Macko, E. (1978) Antagonism of fenfluramine-induced hyperthermia: a measure of central serotonin inhibition. Life Sciences, 22, 1439.
Ugedo, L., Grenhoff, J. & Svensson, T. H. (1989) Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition. Psychopharmacology, 98 4550.
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, 610614.
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.

Related content

Powered by UNSILO

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

  • Herbert Y. Meltzer (a1)

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.

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

  • Herbert Y. Meltzer (a1)
Submit a response

eLetters

No eLetters have been published for this article.

×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *