Investigation of the effects of tamoxifen and glutamate and glutamine levels in brain regions in sleep deprivation-induced mania model in mice

Protein kinase C inhibitor tamoxifen exerts antimanic effect in bipolar patients and reduces mania-like behavior in animals. In mania, it has been shown that protein kinase C activity, glutamate levels and glutamate/glutamine ratio increase in brain regions and decrease in response to treatment. Glutamate has an important role in the modulation of learning and memory formation. Since tamoxifen can reduce glutamate release, it can be suggested that this effect while contributing to the antimanic activity may alter the memory and learning impairment accompanying to mania. In the present study, mice treated with 1 mg/kg tamoxifen twice daily for 8 days were administered REM sleep deprivation 3 times with an interval of 2 days. Locomotor activity was measured 24 hours after the second sleep deprivation. Locomotor activity, risk taking behavior in the staircase test and memory in the novel object recognition test were assessed immediately after the last sleep deprivation and then glutamate and glutamine levels were determined in the frontal cortex and hippocampus. After the second sleep deprivation, the number of squares crossed increased. The number of squares crossed and the number of steps climbed increased, and glutamate decreased in the frontal cortex after the last sleep deprivation. There were no changes in the recognition index value, the amount of glutamine in the frontal cortex, the amount of glutamate and glutamine in the hippocampus and glutamate/glutamine ratio in both regions. REM sleep deprivation-induced increase in locomotor activity and risk-taking behavior and decrease in glutamate level in the frontal cortex were prevented by tamoxifen. Although the findings are contrary to the claims about the relationship between mania, tamoxifen and glutamate, they indicate that glutamate may play a role in the antimanic effect of tamoxifen and suggest that repeated sleep deprivation may better mimic the development of the disorder. These results require further studies to be supported. Key Words: tamoxifen, mania, sleep deprivation, glutamate, learning, memory The present work was supported by the Research Fund of Istanbul University. Project No: 31202