Abstract
Protein kinase C inhibitor tamoxifen reduces symptoms of acute mania in bipolar patients and mania-like behaviors in animals. Memory impairment and altered levels of glutamate and glutamate/glutamine ratio have been reported in mania. Tamoxifen suppresses glutamate release which plays an important role in memory. The present study evaluated whether tamoxifen’s activity participates in its antimanic efficacy in repeated sleep deprivation mania model. Mice were divided into control and 24-h sleep-deprived groups and were treated with vehicle or 1 mg/kg tamoxifen twice daily for 8 days. Sleep deprivation was repeated three times at intervals of 2 days. Square crossing and rearing were recorded as measures of locomotor activity. Memory and risk taking behavior were evaluated using novel object recognition and staircase tests, respectively. Glutamate and glutamine levels were measured in the frontal cortex and hippocampus. Behavioral tests were conducted 24 h after the second or immediately after the third sleep deprivations. Sleep deprivation increased locomotor activity and risk taking. Glutamate and glutamine levels and glutamate/glutamine ratio in the frontal cortex and hippocampus were unaffected. Locomotor hyperactivity was prevented by tamoxifen treatment. No change in the recognition index suggested lack of memory impairment in the model. These findings confirm the relevance of repeated sleep deprivation as a mania model and tamoxifen as an antimanic agent. However, future research is needed to further address lack of memory impairment in the model and lack of glutamatergic influence on the model and antimanic effect of tamoxifen.
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This work was supported by the Scientific Research Projects Coordination Unit of Istanbul University (project number 31202).
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Conceptualization and design of the study: Selda Özakman and Nurhan Enginar.
Data acquisition: Selda Özakman, Nurhan Enginar, M. Zafer Gören, Asiye Nurten, Nurdan Tekin, and Rivaze Kalaycı.
Analysis and interpretation of data: Selda Özakman, Nurhan Enginar, Asiye Nurten and M. Zafer Gören.
Preparation of the first draft of the manuscript: Selda Özakman and Nurhan Enginar.
Reviewing and editing the final manuscript: Nurhan Enginar.
All authors commented on all versions of the manuscript and read and approved the final manuscript.
Supervision: Nurhan Enginar.
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Fig. S1
The overlay of three chromatogram traces of external standards of 0.5 μM, 1 μM and 2.5 μM glutamate and glutamine mixture. The retention times of glutamate and glutamine were 8.28 ± 0.07 and 17.76 ± 0.02 min, respectively. The inlet trace on the upper right hand side belongs to a sample. The chromatogram duration was 40 min where the figure was cut at 20 min. The goodness-of-fit (r2) calculated by linear analyses were 0.9998 and 0.9990, for glutamate and glutamine, respectively. LU: luminescence units. (PDF 62 kb)
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Özakman, S., Gören, M.Z., Nurten, A. et al. Effects of tamoxifen and glutamate and glutamine levels in brain regions in repeated sleep deprivation–induced mania model in mice. Naunyn-Schmiedeberg's Arch Pharmacol 394, 619–629 (2021). https://doi.org/10.1007/s00210-020-02001-1
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DOI: https://doi.org/10.1007/s00210-020-02001-1