Changes in GABA_A receptor subunit expression in the midbrain during the oestrous cycle in Wistar rats

In women, the late luteal phase or "premenstrual" period is commonly associated with psychological disturbances, which include mood changes and increased aggression. The underlying cause is unknown but one possibility is that fluctuations in levels of neuroactive steroids precipitate changes in expression of GABA_A receptor subunits that result in functional changes in inhibitory control systems. The present study investigated the levels of expression of α4, β1 and δ GABA_A receptor subunits in the periaqueductal gray matter (PAG) in rats and whether plasticity occurs during the oestrous cycle in females. In male rats α4, β1 and δ subunit immunoreactive neurones were present throughout the PAG in similar numbers. In female rats in proestrus, oestrus and early dioestrus, the density of α4, β1 and δ subunit immunoreactive cells was similar to males. However, in late dioestrus, the numbers increased significantly, especially in the dorsolateral PAG, a region which is particularly rich in GABAergic interneurones. These parallel changes may reflect an increase in expression of the α4β1δ GABA_A receptor subtype. Recombinant α4β1δ receptors, expressed in Xenopus oocytes, exhibited and EC₅₀ for GABA an order of magnitude lower (2.02±0.33 μM; mean±S.E.M.) than that found for the most ubiquitous α1β2γ2 GABA_A receptor (32.8±2.5 μM). Increased expression of α4β1δ GABA_A receptors in the interneurones of the PAG could render the panic circuitry abnormally excitable by disinhibiting the ongoing GABAergic inhibition. Similar changes in neuronal excitability within the PAG in women consequent to falling steroid levels in the late luteal phase of the menstrual cycle could contribute to the development of pre-menstrual dysphoria.