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Olanzapine: a basic science update

  • Franklin Bymaster (a1), Kenneth W. Perry (a1), David L. Nelson (a1), David T. Wong (a1), Kurt Rasmussen (a1), Nick A. Moore (a1) and David O. Calligaro (a1)...

Abstract

Olanzapine, an atypical antipsychotic, has a broad receptor binding profile, which may account for its pharmacological effects in schizophrenia. In vitro receptor binding studies showed a high affinity for dopamine D2, D3, and D4 receptors; all 5-HT2 receptor subtypes and the 5-HT6 receptor; muscarinic receptors, especially the M1 subtype; and α1-adrenergic receptors. In vivo studies showed that olanzapine had potent activity at D2 and 5 -HT2A receptors, but much less activity at D1 and muscarinic receptors, and that it inhibited dopaminergic neurons in the A10 but not the A9 tract, suggesting that this agent will not cause extrapyramidal side-effects (EPS). Microdialysis studies showed that olanzapine increased the extracellular levels of norepinephrine and dopamine, but not 5-HT, in the prefrontal cortex, and increased extracellular dopamine levels in the neostriatum and nucleus accumbens, areas ofthe brain associated with schizophrenia. Studies of gene expression showed that olanzapine 10 mg/kg also increased Fos expression in the prefrontal cortex, the dorsolateral striatum, and the nucleus accumbens. These findings are consistent with the effectiveness of olanzapine on both negative and positive symptoms and suggest that, with careful dosing, olanzapine should not cause EPS.

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Corresponding author

Correspondence: F. Bymaster, Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285 0510, USA

References

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Bymaster, F. P., Calligaro, D. O., Marsh, R. D., et al (1996a) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology, 14, 8796.
Bymaster, F. P., Hemrick-Luecke, S. K., Perry, K. W., et al (1996b) Neurochemical evidence for antagonism by olanzapine of dopamine, serotonin, 0,-adrenergic and muscarinic receptors in vivo in rats. Psychopharmacology, 124, 8794.
Bymaster, F. P., Nelson, D. L., DeLapp, N. W., et al (1996c) The atypical antipsychotic olanzapine is an antagonist at dopamine, serotonin and muscarinic receptor subtypes. Schizophrenia Research, 18, 139.
Bymaster, F. P., Bymaster, L., Bymaster, X.-M., Carter, P. A., et al (1997a) Olanzapine increases extracellular dopamine release and blocks dopamine, serotonin and muscarinic receptors in vivo. Schizophrenia Research, 24, 74.
Bymaster, F. P., Rasmussen, K., Calligaro, D. O., et al (1997b) In vitro and in vivo biochemistry of olanzapine: a novel, atypical antipsychotic drug. Journal of Clinical Psychiatry, 58 (suppl. 10), 2836.
Calligaro, D., Fairhurst, J., Hotten, T. M., et al (1996) The synthesis and biological activity of some known metabolites of the atypical antipsychotic agent olanzapine (LY170053). Biorganic Medicinal Chemistry Letters, 7, 2530.
Deutch, A. Y. (1992) The regulation of subcortical dopamine systems by the prefrontal cortex: interactions of central dopamine systems and the pathogenesis of schizophrenia. Journal of Neural Transmission, 36 (suppl.), 6189.
Fuller, R. W. & Snoddy, H. D. (1992) Neuroendocrine evidence for antagonism of serotonin and dopamine receptors by olanzapine, an antipsychotic drug candidate. Research Communications in Chemical Pathology and Pharmacology, 77, 8793.
Li, X.-M., Perry, K.W., Wong, D. T., et al (1998) Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum. Psychopharmacology, 136, 153161.
Lucaites, V. L., Bymaster, F. P., Wainscott, D. B., et al (1995) Olanzapine exhibits similar activities to clozapine at cloned human serotonin 2A, 2B, 2C and muscarinic receptors. Society of Neuroscience Abstracts, 21, 1125.
Robertson, G. S. & Fibiger, H. C. (1992) Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine. Neuroscience, 46, 315328.
Robertson, G. S. & Fibiger, H. C. (1996) Effects of olanzapine on regional c-fos expression in rat forebrain. Neuropsychopharmacology, 14, 105110.
Roth, B. L., Craigo, S. C., Choudhary, M. S., et al (1994) Binding of typical and atypical antipsychotic agents to (5-hydroxytryptamine)6 and (5-hydroxytryptamine)7 receptors. Journal of Pharmacology and Experimental Therapeutics, 268, 14031410.
Schickler, E. & Marr, I. (1996) The moderate affinity of clozapine at H3 receptors is not shared by its two major metabolites and by structurally related and unrelated atypical neuroleptics. Naunyn-Schmiedebergs Archives of Pharmacology, 353, 290294.
Schotte, A., Janssen, P. F. M., Gommeren, W., et al (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology, 124, 5773.
Skarsfeldt, T. (1995) Differential effects of repeated administration of novel antipsychotic drugs on the activity of midbrain dopamine neurons in the rat. European Journal of Pharmacology, 281, 289294.
Stockton, M. E. & Rasmussen, K. (1996) Electrophysiological effects of olanzapine, a novel atypical antipsychotic, on A9 and A10 dopamine neurons. Neuropsychopharmacology, 14, 97104.
Zeng, P. X., Le, F. & Richelson, E. (1997) Muscarinic M4 receptor activation by some atypical antipsychotic drugs. European Journal of Pharmacology, 321, 349354.

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Olanzapine: a basic science update

  • Franklin Bymaster (a1), Kenneth W. Perry (a1), David L. Nelson (a1), David T. Wong (a1), Kurt Rasmussen (a1), Nick A. Moore (a1) and David O. Calligaro (a1)...
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