Plasticity of GABAA receptor subunit expression during the oestrous cycle of the rat: implications for premenstrual syndrome in women

Abstract

Many women experience psychological changes during the luteal phase of their menstrual cycle. The late luteal (premenstrual) phase, when symptoms become most severe, is characterized by declining levels of ovarian progesterone. In female rats, withdrawal from prolonged dosing with progesterone leads to upregulation of alpha4 and delta subunits of the GABAA receptor in several brain regions. During the oestrous cycle of the rat, the natural fall in progesterone that occurs in late dioestrus is associated with a parallel increase in expression of alpha4, beta1 and delta GABAA receptor subunits in neurones in the periaqueductal grey matter (PAG), suggesting that new receptors of the alpha4beta1delta composition have been formed. Recombinant alpha4beta1delta receptors display a low EC50 for GABA, which is consistent with activation by extracellular levels of GABA. They are also likely to be located extrasynaptically and to carry tonic currents. In the PAG, a region involved in mediating panic-like anxiety, alpha4, beta1 and delta GABAA receptor subunits are located principally on GABAergic interneurones. On-going GABAergic neuronal activity normally limits and controls the excitability of the panic circuitry. During late dioestrus, when expression of alpha4, beta1 and delta subunits on GABAergic interneurones is upregulated, the increase in tonic current would be expected to lead to a reduction in the activity of the GABAergic population. Thus the panic circuitry would become intrinsically more excitable. It is suggested that during the menstrual cycle in women, plasticity of GABAA receptor subunit expression in brain regions such as the PAG, which are involved in mediating anxiety behaviour, may underlie some of the changes in mood that occur during the premenstrual period.