Neuroactive steroids and GABAA receptor plasticity during the oestrous cycle

多达80%的女性在月经前会出现情绪波动、易怒和焦虑等不良心理症状。症状其他疾病状态，如恐慌症，月经性癫痫和肠易激综合征，往往在月经期间变得更糟。所有这些变化都会对妇女的社会、家庭和工作生活产生重大影响。目前的治疗方法通常包括每日服用选择性5-羟色胺受体阻滞剂（SSRIs）。虽然有效，但长期治疗后往往会出现副作用。此外，SSRIs抑制经前症状的确切方式尚不清楚，部分原因是我们还不完全了解经前症状是如何发展的。然而，最近对老鼠的研究已经开始阐明这个问题。雌性大鼠在其发情周期的后半段（相当于月经周期）表现出焦虑水平的增加，并且似乎焦虑的增加可能是由性激素孕酮的分解产物（称为别孕烯醇酮）的水平下降引发的，这导致大脑区域中与产生焦虑样行为有关的抑制性神经细胞的活动减少。因此，这些神经回路和焦虑水平的兴奋性增加。该项目的目的是找出是否可以开发间歇性给药的药物，可以提高大脑中的alopregnanolone水平，以防止与发情周期相关的大脑回路兴奋性的变化，这些变化是焦虑增加的基础。

Up to 80% of women experience adverse psychological symptoms such as mood swings, irritability and anxiety, during their premenstrual period. The symptoms other disease states such as panic disorder, catamenial epilepsy and irritable bowel syndrome, often get worse during the menstrual period. All these changes can impact significantly on the social, family and working lives of women. Current treatments usually involve taking daily doses of selective serotonin reputake blockers (SSRIs). Although effective, side effects often develop after long-term treatment. Moreover, the exact way that SSRIs work to suppress premenstrual symptoms is not known, partly because we do not yet fully understand how premenstrual symptoms develop. However, recent studies using rats have started to shed some light on this question. Female rats show increases in anxiety levels during the latter half of their oestrous cycle (equivalent to the menstrual cycle) and it appears that the increased anxiety may be triggered by falling levels of a breakdown product of the sex hormone progesterone, called allopregnanolone, which leads to a decrease in the activity of inhibitory nerve cells in regions of the brain that are concerned with generating anxiety-like behaviours. As a consequence, the excitability of these neural circuits and of anxiety levels, increases. The aim of this project is to find out whether intermittent dosing with drugs that can raise brain levels of allopregnanolone could be developed to prevent the oestrous cycle-related changes in excitability of the circuits in the brain that underlie the development of increased anxiety.