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Clozapine's Antipsychotic Effects do not Depend on Blockade of 5-HT3 Receptors

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Abstract

Sixteen known 5-HT3 receptor blockers, including clozapine, fully or partially reverse the inhibitory effect of 1 μM GABA on [35S]TBPS binding, indicating that they are also GABAA antagonists, some of them selective for subsets of GABAA receptors. The 5-HT3 receptor blocker, ondansetron, has been reported to produce some antipsychotic and anxiolytic effects. However, no antipsychotic effects have been reported for a large number of highly potent 5-HT3 receptor blockers. Like clozapine, ondansetron partially reverses the inhibitory effect of GABA on [35S]TBPS binding. Additivity experiments suggest that ten 5-HT3 receptor blockers tested at low concentrations preferentially block subtypes of GABAA receptors that are among those blocked by clozapine. Wiley and Porter (29) reported that MDL-72222, the most potent GABAA antagonist decribed here, partially generalizes (71%) with clozapine in rats trained to discriminate an interoceptive clozapine stimulus, but only at a dose that severly decreases responding. Tropisetron (ICS-205,930) exhibits both GABA-positive and GABA-negative effects. R-(+)-zacopride is 6-fold more potent than S-(−)-zacopride as a GABAA antagonist. We conclude that the observed antipsychotic and, possibly, anxiolytic effects of some 5-HT3 receptor blockers are due to selective antagonism of certain GABAA receptors, and not to blockade of 5-HT3 receptors. We speculate that the anxiolytic and sedative effects of clozapine and several other antipsychotic drugs may be due to selective blockade of α1β2γ2 GABAA receptors which are preferentially located on certain types of GABAergic interneurons (probably parvalbumin positive). Blockade of these receptors will increase the inhibitory output of these interneurons. So far, no highly potent GABAA antagonists with clozapine-like selectivity have been identified. Such compounds may exhibit improved clozapine-like antipsychotic activity.

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REFERENCES

  1. Maricq, A. V., Peterson, A. S., Brake, A. J., Myers, R. M., and Julius, D. 1991. Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Science 254:432–437.

    Google Scholar 

  2. Squires, R. F., and Saederup, E. 1987. GABAA receptor blockers reverse the inhibitory effect of GABA on brain-specific [35S]TBPS binding. Brain Res. 414:357–364.

    Google Scholar 

  3. Kilpatrick, G. J., Bunce, K. T., and Tyers, M. B. 1990. 5-HT3 Receptors. Med. Res. Rev. 10:441–475.

    Google Scholar 

  4. Hunt, P., and Clements-Jewery, S. 1981. A steroid derivative, R 5135, antagonizes the GABA/benzodiazepine receptor interaction. Neuropharmacol. 20:357–361.

    Google Scholar 

  5. Curtis, D. R., and Malick, R. 1985. Glycine antagonism by RU 5135. Eur. J. Pharmacol. 110:383–384.

    Google Scholar 

  6. Gerlach, J. 1991. New antipsychotics: Classification, effiacy, and adverse effects. Schizophrenia Bull. 17:289–309.

    Google Scholar 

  7. White, A., Corn, T. H., Feetham C., and Faulconbridge, C. 1991. Ondansetron in the treatment of schizophrenia. Lancet 337:1173.

    Google Scholar 

  8. Bentley, K. R., and Barnes, N. M. 1995. Therapeutic potential of serotonin 5-HT3 antagonists in neuropsychiatric disorders. CNS Drugs 3:363–392.

    Google Scholar 

  9. Ye, J. H., Hunt, T., Wu, W-H., and McArdle, J. J. 1997. Ondansetron modulates GABAA current of rat central nervous system neurons. Eur. J. Pharmacol. 337:87–94.

    Google Scholar 

  10. Watling, K. J., Beer, M. S., Stanton, J. A., and Newberry, N. R. 1990. Interaction of the atypical neuroleptic clozapine with 5-HT3 receptors in the cerebral cortex and superior cervical ganglion of the rat. Eur. J. Pharmacol. 182:465–472.

    Google Scholar 

  11. Squires, R. F., and Saederup, E. 1991. A review of evidence for GABergic predominance/glutamatergic deficit as a common etiological factor in both schizophrenia and affective psychoses: More support for a continuum hypothesis of “functional” psychosis. Neurochem. Res. 16:1099–1111.

    Google Scholar 

  12. Squires, R. F., and Saederup, E. 1997. Clozapine and some other antipsychotic drugs may preferentially block the same subset of GABAA receptors. Neurochem. Res. 22:151–162.

    Google Scholar 

  13. Korpi, E. R., Wong, G., and Lüddens, H. 1995. Subtype specificity of γ-aminobutyric acid type A receptor antagonism by clozapine. N-S. Arch. Pharmacol. 352:365–373.

    Google Scholar 

  14. Squires, R. F., and Saederup, E. 1998. Clozapine and several other antipsychotic/antidepressant drugs preferentially block the same ‘core’ fraction of GABAA receptors. Neurochem. Res. 23:1283–1290.

    Google Scholar 

  15. Squires, R. F., Casida, J. E., Richardson, M., and Saederup, E. 1983. [35S]t-Butylbicyclophosphorothionate binds with high affinity to brain-specific sites coupled to γ-aminobutyric acid-A and ion recognition sites. Mol. Pharmacol. 23:326–336.

    Google Scholar 

  16. Seifert, J., and Casida, J. E. 1985. Solubilization and detergent effects on interactions of some drugs and insecticides with the t-butylbicyclophosphorothionate binding site within the γ-aminobutyric acid receptor-ionophore complex. J. Neurochem. 44:110–116.

    Google Scholar 

  17. Nielsen, M., Honore, T., and Braestrup, C. 1985. Radiation inactivation of brain [35S]t-butylbicyclophosphorothionate binding sites reveals complicated molecular arrangements of the GABA/ benzodiazepine receptor chloride channel complex. Biochem. Pharmacol. 34:3633–3642.

    Google Scholar 

  18. Wisden, W., Laurie, D. J., Monyer, H., and Seeburg, P. H. 1992. The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. telencephalon, diencephalon, mesencephalon. J. Neurosci. 12:1040–1062.

    Google Scholar 

  19. Benke, D., Fritschy, J-M., Trzeciak, A., Bannwarth, W., and Mohler, H. 1994. Distribution, prevalence, and drug binding profile of γ-aminobutyric acid type A receptor subtypes differing in the β-subunit variant. J. Biol. Chem. 269:27100–27107.

    Google Scholar 

  20. Fritschy, J-M., and Mohler, H. 1995. GABAA-receptor heterogeneity in the adult rat brain differential regional and cellular distribution of seven major subunits. J. Comp. Neurol. 359:154–194.

    Google Scholar 

  21. McKernan, R. M., and Whiting, P. J. 1996. Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci. 19:139–143.

    Google Scholar 

  22. Ducic, I., Caruncho, H. J., Zhu, W. J., Vicini, S., and Costa, E. 1995. γ-Aminobutyric acid gating of C1-channels in recombinant GABAA receptors. J. Pharmacol. Exp. Ther. 272:438–445.

    Google Scholar 

  23. Fozard, J. R., Mobarok Ali, A. T. M., and Newgrosh, G. 1979. Blockade of serotonin receptors on autonomic neurones by (-)-cocaine and some related compounds. Eur. J. Pharmacol. 59:195–210.

    Google Scholar 

  24. Fozard, J. R., and Gittos, M. W. 1983. Selective blockade of 5-hydroxytryptamine neuronal receptors by benzoic acid esters of tropine. Br. J. Pharmacol. 80:511P.

    Google Scholar 

  25. Klein, R. L., Sanna, E., McQuilkin, S. J., Whiting, P. J., and Harris, R. A. 1994. Effects of 5-HT3 receptor antagonists on binding and function of mouse and human GABAA receptors. Eur. J. Pharmacol. Mol. Pharm. 268:237–246.

    Google Scholar 

  26. Fan, P. 1994. Mepacrine-induced inhibition of the inward current mediated by 5-HT3 receptors in rat nodose ganglion neurones. Br. J. Pharmacol. 112:745–748.

    Google Scholar 

  27. Squires, R. F., and Saederup, E. 1993. Mono N-aryl ethlylenediamine and piperazine derivatives are GABAA receptor blockers: implications for psychiatry. Neurochem. Res. 18:787–793.

    Google Scholar 

  28. von Blankenfeld, G., Ymer, S., Pritchett, D. B., Sontheimer, H., Ewert, M., Seeburg, P. H., and Kettenmann, H. 1990. Differential benzodiazepine pharmacology of mammalian recombinant GABAA receptors. Neurosi. Lett. 115:269–273.

    Google Scholar 

  29. Wiley, J. L., and Porter, J. H. 1992. Serotonergic drugs do not substitute for clozapine-trained rats in a two-lever drug discrimination procedure. Pharmacol. Bioch. Behav. 43:961–965.

    Google Scholar 

  30. Young, R., and Johnson, D. N. 1991. Anxiolytic-like activity of R(+)-and S(−)-zacopride in mice. Eur. J. Pharmacol. 201:151–155.

    Google Scholar 

  31. Kidd, E. J., Levy, J. C., Nielsen, M., Hamon, M., and Gozlan, H. 1993. Characterisation of the non-5-HT3 high-affinity ‘R’ binding site for (R)-zacopride in brain and other tissues. Eur. J. Pharmacol. Mol. Pharm. 247:45–56.

    Google Scholar 

  32. Gao, B., and Fritschy, J. M. 1994. Selective allocation of GABAA receptors containing the α1 subunit to neurochemically distinct subpopulations of rat hippocampal interneurons. Eur J Neurosci 6:837–853.

    Google Scholar 

  33. Freund, T. F., and Meskenaite, V. 1992. γ-Aminobutyric acid-containing basal forebrain neurons innervate inhibitory interneurons in the neocortex. Proc. Natl. Acad. Sci. 89:738–742.

    Google Scholar 

  34. DeFelipe, J., Hendry, S. H. C., and Jones, E. G. 1989. Visualization of chandelier cell axons by parvalbumin immunoreactivity in monkey cerebral cortex. Proc. Natl. Acad. Sci. 86:2093–2097.

    Google Scholar 

  35. Gulyás, A. I., Hájos, N., and Freund, T. F. 1996. Interneurons containing calretinin are specialized to control other interneurons in the rat hippocampus. J. Nerosci. 16:3397–3411.

    Google Scholar 

  36. Farnbach-Pralong, D., Bradbury, R., Copolov, D., and Dean, B. 1998. Clozapine and olanzapine treatment decreases rat cortical and limbic GABAA receptors. Eur. J. Pharmacol. 349:R7–R8.

    Google Scholar 

  37. Schoch, P., Richards, J. G., Häring, P., Takacs, B., Stähli, C., Staehelin, T., Haefely, W., and Möhler, H. 1985. Co-localization of GABAA receptors and benzodiazepine receptors in the brain shown by monoclonal antibodies. Nature 314:168–171.

    Google Scholar 

  38. Carlsson, A., and Linquist, M. 1963. Effect of chlorpromazine and haloperidol on formation of 3-methoxy-tyramine and normetanephrine in mouse brain. Acta Pharmcol. Toxicol. 20:140–144.

    Google Scholar 

  39. Hippius, H. 1989. The history of clozapine, Psychopharmacol. 99: S3–S5.

    Google Scholar 

  40. Tandon, R., Goldman, R., DeQuardo, J. R., Goldman, M., Perez, M., and Jibson, M. 1993. Positive and negative symptoms covary during clozapine treatment in schizophrenia. J Psychiat Res 27:341–347.

    Google Scholar 

  41. Miller, D. D., Perry, P. J., Cadoret, R. J., and Andreasen, N. C. 1994. Clozapine's effect on negative symptoms in treatment-refractory schizophrenics. Comp. Psychiat. 35:8–15.

    Google Scholar 

  42. McKenna, P. J., and Bailey, P. E. 1993. The strange story of clozapine. Br J Psychiat 162:32–37.

    Google Scholar 

  43. Baldessarini, R. J., Centorrino, F., Flood, J. G., Volpicelli, S. A., Huston-Lyons, D., and Cohen, B. M. 1993. Tissue concentrations of clozapine and its metabolites in the rat. Neuropsychopharmacology 9:117–124.

    Google Scholar 

  44. Bymaster, F. P., Calligaro, D. O., Falcone, J. F., Marsh, R. D., Moore, N. A., Tye, N. C., Seeman, P., and Wong, D. T. 1996. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharm. 14:87–96.

    Google Scholar 

  45. Bristow, L. J., Kramer, M. S., Kulagowski, J., Patel, S., Ragan, C. I., and Seabrook, G. R. Schizophrenia and L-745,870, a novel dopamine D4 receptor antagonist. TiPS 18:186–188.

  46. Monge, A., Palop, J. A., Del Castillo, J. C., Caldero, J. M., Roca, J., Romero, G., Del Rio, J., and Lasheras, B. 1993. Novel antagonists of 5-HT3 receptors. Synthesis and biological evaluation of piperazinylquinoxaline derivatives. J. Med. Chem. 36:2745–2750.

    Google Scholar 

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  1. The Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY, 10962

    Richard F. Squires & Else Saederup

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  1. Richard F. Squires
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Squires, R.F., Saederup, E. Clozapine's Antipsychotic Effects do not Depend on Blockade of 5-HT3 Receptors. Neurochem Res 24, 659–667 (1999). https://doi.org/10.1023/A:1021052409140

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