Neuroactive steroids and GABAA receptor plasticity during the oestrous cycle

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.

Premenstual symptoms blight the lives of up to 80% of women of reproductive age. Using the rat as a model, we have shown that the natural fall in plasma progesterone that occurs during late dioestrus (similar to the premenstrual period in women, leads upregulation of alpha4, beta1 and delta GABAA receptor subunit expression and a decrease in ongoing GABAergic tone in the periaqueductal grey matter (PAG), a region involved in generation of panic-like anxiety. These changes may underlie the increase in anxiety behaviour that develops during late dioestrus.
The object of the new study is to determine whether acute administration of a steroidogenic agent can offset the natural fall in steroid levels that occurs during late dioestrus and so prevent the development of oestrous cycle-related anxiety.
Using a multidisciplinary approach, we will determine firstly whether the steroidogenic compound
fluoxetine can prevent progesterone withdrawal-evoked
a) decrease in brain allopregnanolone levels
b) upregulation of GABAA receptor subunit expression in the PAG
c) decrease in GABAergic tone in the PAG
d) increase in panic-like anxiety behaviour
In the second phase of the work we will go on to investigate the effectiveness of fluoxetine in preventing these changes during the natural fall in progesterone that occurs during late dioestrus in spontaneously cycling rats.
The findings from this study will have implications for the development of new therapeutic strategies for treatment of premenstrual disorders in women.