Olanzapine ameliorated cognition deficit in a schizophrenia mouse model
DOI:
https://doi.org/10.60988/p.v36i2.9Keywords:
Olanzapine, Schizophrenia, Cognitive deficit, T-mazeAbstract
Background: Cognitive impairment is a core feature of schizophrenia that greatly impacts functioning. Typical antipsychotics do not improve cognition, but some evidence suggests certain atypical antipsychotics like olanzapine may benefit aspects of cognition at optimal doses. This study investigated the dose-dependent cognitive effects of the atypical antipsychotic olanzapine in a mouse model of schizophrenia. Methods: Mice were housed socially or in isolation from weaning to induce schizophrenia-related deficits. Isolated adult mice were treated chronically with olanzapine at doses of 0, 0.5, 1.3, or 5 mg/kg (n=10/group) for 4 weeks. Locomotor activity, recognition memory (novel object recognition test), and working memory (T-maze alternation) were assessed. Results: Isolation increased locomotor activity and impaired recognition and working memory versus social controls. Olanzapine doses of 0.5 and 1.3 mg/kg partially attenuated hyper locomotion. Low doses also improved recognition memory and T-maze performance, suggesting cognitive enhancement. However, the highest 5 mg/kg dose decreased locomotion and recognition memory, indicating potential sedative effects at excessive doses. Conclusions: This study provides preclinical evidence that olanzapine at appropriate low to moderate doses can reverse cognitive deficits in animal models relevant to schizophrenia. However, higher doses may cause sedation and cognitive impairment. Careful optimization of olanzapine dosing may be crucial for mitigating symptoms while improving cognition in schizophrenia.
References
Kahn, R. S., Sommer, I. E., Murray, R. M., Meyer-Lindenberg, A., Weinberger, D. R., Cannon, T. D., ... & Insel, T. R. (2015). Schizophrenia (Primer). Nature Reviews: Disease Primers, 1(1).
Buchanan RW. Persistent negative symptoms in schizophrenia: an overview. Schizophrenia bulletin. 2007 Jul 1;33(4):1013-22.
WHO. Schizophrenia [Internet]. 2022. Available from: https://www.who.int/news-room/fact-sheets/detail/schizophrenia
Mueser, K.T., McGurk, S.R. Schizophrenia. Lancet [Internet]. 2004;363(9426):2063–72. Available from: https://www.sciencedirect.com/science/article/pii/S0140673604164581
Lehman, A. F., Lieberman, J. A., Dixon, L. B., McGlashan, T. H., Miller, A. L., Perkins, D. O., & Kreyenbuhl, J. (2004). American Psychiatric Association Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry, 161(2 Suppl), 1-56.
Kane, J.M., Correll, C.U. Pharmacologic treatment of schizophrenia. Dialogues Clin Neurosci [Internet]. 2010 [cited 2023 Jul 8];12(3):345–57. Available from: https://www.tandfonline.com/action/journalInformation?journalCode=tdcn20
Maroney, M. (2020). An update on current treatment strategies and emerging agents for the management of schizophrenia. Am J Manag Care, 26(3 Suppl), S55-S61.
Bymaster, F. P., Hemrick-Luecke, S. K., Perry, K. W., & Fuller, R. W. (1996). Neurochemical evidence for antagonism by olanzapine of dopamine, serotonin, α 1-adrenergic and muscarinic receptors in vivo in rats. Psychopharmacology, 124, 87-94.
Meltzer, H. Y., & McGurk, S. R. (1999). The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophrenia bulletin, 25(2), 233-256.
Cuesta, M. J., Peralta, V., & Zarzuela, A. (2001). Effects of olanzapine and other antipsychotics on cognitive function in chronic schizophrenia: a longitudinal study. Schizophrenia research, 48(1), 17-28.
Harvey, P. D., & Keefe, R. S. (2001). Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. American journal of psychiatry, 158(2), 176-184.
Lee, M. A., Jayathilake, K., & Meltzer, H. Y. (1999). A comparison of the effect of clozapine with typical neuroleptics on cognitive function in neuroleptic-responsive schizophrenia. Schizophrenia research, 37(1), 1-11.
Green, M. F., Marder, S. R., Glynn, S. M., McGurk, S. R., Wirshing, W. C., Wirshing, D. A., ... & Mintz, J. (2002). The neurocognitive effects of low-dose haloperidol: a two-year comparison with risperidone. Biological psychiatry, 51(12), 972-978.
Hill, S. K., Bishop, J. R., Palumbo, D., & Sweeney, J. A. (2010). Effect of second-generation antipsychotics on cognition: current issues and future challenges. Expert review of neurotherapeutics, 10(1), 43-57.
McGurk, S. R., Lee, M. A., Jayathilake, K., & Meltzer, H. Y. (2004). Cognitive effects of olanzapine treatment in schizophrenia. Medscape General Medicine, 6(2).
Malik, J. A., Yaseen, Z., Thotapalli, L., Ahmed, S., Shaikh, M. F., & Anwar, S. (2023). Understanding translational research in schizophrenia: A novel insight into animal models. Molecular Biology Reports, 50(4), 3767-3785.
Antunes, M., & Biala, G. (2012). The novel object recognition memory: neurobiology, test procedure, and its modifications. Cognitive processing, 13, 93-110.
Janczura, K. J., Olszewski, R. T., Bzdega, T., Bacich, D. J., Heston, W. D., & Neale, J. H. (2013). NAAG peptidase inhibitors and deletion of NAAG peptidase gene enhance memory in novel object recognition test. European journal of pharmacology, 701(1-3), 27-32.
Deacon, R. M., & Rawlins, J. N. P. (2006). T-maze alternation in the rodent. Nature protocols, 1(1), 7-12.
Green, M. F., Kern, R. S., & Heaton, R. K. (2004). Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophrenia research, 72(1), 41-51.
Lepage, M., Bodnar, M., & Bowie, C. R. (2014). Neurocognition: clinical and functional outcomes in schizophrenia. The Canadian Journal of Psychiatry, 59(1), 5-12.
Gaskin, P. L., Alexander, S. P., & Fone, K. C. (2014). Neonatal phencyclidine administration and post-weaning social isolation as a dual-hit model of ‘schizophrenia-like’behaviour in the rat. Psychopharmacology, 231, 2533-2545.
Silva-Gómez, A. B., Rojas, D., Juarez, I., & Flores, G. (2003). Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats. Brain research, 983(1-2), 128-136.
Sams-Dodd, F. (1997). isolation in the rat social interaction test. Behavioural pharmacology, 8, 196-215.
Gleason, S. D., & Shannon, H. E. (1997). Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice. Psychopharmacology, 129, 79-84.
Liang, L., Ren, X., Xu, J., Ma, Y., Xue, Y., Zhuang, T., & Zhang, G. (2022). Effect of co-treatment of olanzapine with SEP-363856 in mice models of schizophrenia. Molecules, 27(8), 2550.
Jones, C. A., Watson, D. J. G., & Fone, K. (2011). Animal models of schizophrenia. British journal of pharmacology, 164(4), 1162-1194.
Kapur, S., Zipursky, R. B., & Remington, G. (1999). Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. American Journal of Psychiatry, 156(2), 286-293.
Ichikawa, J., Ishii, H., Bonaccorso, S., Fowler, W. L., O'Laughlin, I. A., & Meltzer, H. Y. (2001). 5‐HT2A and D2 receptor blockade increases cortical DA release via 5‐HT1A receptor activation: a possible mechanism of atypical antipsychotic‐induced cortical dopamine release. Journal of neurochemistry, 76(5), 1521-1531.
Kapur, S., Zipursky, R., Jones, C., Remington, G., & Houle, S. (2000). Relationship between dopamine D2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. American journal of psychiatry, 157(4), 514-520.
Bymaster, F. P., Nelson, D. L., DeLapp, N. W., Falcone, J. F., Eckols, K., Truex, L. L., ... & Calligaro, D. O. (1999). Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and α1-adrenergic receptors in vitro. Schizophrenia research, 37(1), 107-122.
Ennaceur, A., & Delacour, J. (1988). A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behavioural brain research, 31(1), 47-59.
Calkins, M. E., Gur, R. C., Ragland, J. D., & Gur, R. E. (2005). Face recognition memory deficits and visual object memory performance in patients with schizophrenia and their relatives. American Journal of Psychiatry, 162(10), 1963-1966.
Mutlu, O., Ulak, G., Celikyurt, I. K., Akar, F. Y., Erden, F., & Tanyeri, P. (2011). Effects of olanzapine, sertindole and clozapine on MK-801 induced visual memory deficits in mice. Pharmacology Biochemistry and Behavior, 99(4), 557-565.
Apam-Castillejos, D. J., Tendilla-Beltrán, H., Vázquez-Roque, R. A., Vázquez-Hernández, A. J., Fuentes-Medel, E., García-Dolores, F., ... & Flores, G. (2022). Second-generation antipsychotic olanzapine attenuates behavioral and prefrontal cortex synaptic plasticity deficits in a neurodevelopmental schizophrenia-related rat model. Journal of Chemical Neuroanatomy, 125, 102166.
Shirazi-Southall, S., Rodriguez, D. E., & Nomikos, G. G. (2002). Effects of typical and atypical antipsychotics and receptor selective compounds on acetylcholine efflux in the hippocampus of the rat. Neuropsychopharmacology, 26(5), 583-594.
Ichikawa, J., Dai, J., O'Laughlin, I. A., Fowler, W. L., & Meltzer, H. Y. (2002). Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum. Neuropsychopharmacology, 26(3), 325-339.
Perry, E., Walker, M., Grace, J., & Perry, R. (1999). Acetylcholine in mind: a neurotransmitter correlate of consciousness?. Trends in neurosciences, 22(6), 273-280.
Winkler, J., Suhr, S. T., Gage, F. H., Thal, L. J., & Fisher, L. J. (1995). Essential role of neocortical acetylcholine in spatial memory. Nature, 375(6531), 484-487.
Li, X. M., Perry, K. W., Wong, D. T., & Bymaster, F. P. (1998). Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum. Psychopharmacology, 136, 153-161.
Cools, R., & D'Esposito, M. (2011). Inverted-U–shaped dopamine actions on human working memory and cognitive control. Biological psychiatry, 69(12), e113-e125.
Song, J. C., Seo, M. K., Park, S. W., Lee, J. G., & Kim, Y. H. (2016). Differential effects of olanzapine and haloperidol on MK-801-induced memory impairment in mice. Clinical Psychopharmacology and Neuroscience, 14(3), 279.
Mutlu, O., Celikyurt, I. K., Ulak, G., Tanyeri, P., Akar, F. Y., & Erden, F. (2012). Effects of olanzapine and clozapine on radial maze performance in naive and MK-801-treated mice. Arzneimittelforschung, 62(01), 4-8.
Mahmoud, G. S., Sayed, S. A., Abdelmawla, S. N., & Amer, M. A. (2019). Positive effects of systemic sodium benzoate and olanzapine treatment on activities of daily life, spatial learning and working memory in ketamine-induced rat model of schizophrenia. International Journal of Physiology, Pathophysiology and Pharmacology, 11(2), 21.
Terry Jr, A. V., Warner, S. E., Vandenhuerk, L., Pillai, A., Mahadik, S. P., Zhang, G., & Bartlett, M. G. (2008). Negative effects of chronic oral chlorpromazine and olanzapine treatment on the performance of tasks designed to assess spatial learning and working memory in rats. Neuroscience, 156(4), 1005-1016..
Upright, N. A., & Baxter, M. G. (2020). Effect of chemogenetic actuator drugs on prefrontal cortex-dependent working memory in nonhuman primates. Neuropsychopharmacology, 45(11), 1793-1798.
Babic, I., Gorak, A., Engel, M., Sellers, D., Else, P., Osborne, A. L., ... & Weston-Green, K. (2018). Liraglutide prevents metabolic side-effects and improves recognition and working memory during antipsychotic treatment in rats. Journal of Psychopharmacology, 32(5), 578-590.
