Study on the role of endogenous neurosteroids in the regulation of GABAergic function and pathophysiology of stress

点击翻译按钮获取中文摘要

In this study, we investigated physiological and pathophysiological roles of an endogenous neurosteroid, allopregnanolone (ALLO), in the regulation of GABAergic system using protracted social isolation mice as an animal model with dysfunction of neurosteroidogenesis system. Social isolation stress and a 5α-reductase inhibitor SKF105111 (SKF) treatment significantly reduced a threshold dose of picrotoxin to induce convulsion in mice. The effect of SKF was significantly reversed by a small dose of ALLO. The present electrophysiological study revealed that the SKF treatment decreased GABA-induced Cl^-currents and GABA-mediated inhibitory postsynaptic currents in normal mice. Protracted social isolation of mice induced a decrease of brain ALLO content in an isolation period-dependent manner and the extent of the decrease was inversely related to the increase of aggressiveness in this animal group. S-and R-Fluoxetine, selective serotonin reuptake inhibitors, reduced ex vivo serotonin uptake into the brain tissue but there was no difference in the potency between these stereoisomers. On the other hand, both S-and R-fluoxetine mitigated aggressiveness and normalized brain ALLO level in socially isolated mice at lower doses than they inhibited serotonin reuptake. Therefore, our study suggested that the brain ALLO content physiologically upregulates the GABA receptor function and that social isolation stress-induces a reduction of brain ALLO probably causally related with the onset of aggression.