Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits

Abstract

Neurosteroids, such as the progesterone metabolite 3α-OH-5α[β]-pregnan-20-one (THP or [allo] pregnanolone), function as potent positive modulators of the GABA A receptor (GABAR) when acutely administered. However, fluctuations in the circulating levels of this steroid at puberty, across endogenous ovarian cycles, during pregnancy or following chronic stress produce periods of prolonged exposure and withdrawal, where changes in GABAR subunit composition may occur as compensatory responses to sustained levels of inhibition. A number of laboratories have demonstrated that both chronic administration of THP as well as its withdrawal transiently increase expression of the α4 subunit of the GABAR in several areas of the central nervous system (CNS) as well as in in vitro neuronal systems. Receptors containing this subunit are insensitive to benzodiazepine (BDZ) modulation and display faster deactivation kinetics, which studies suggest underlie hyperexcitability states. Similar increases in α4 expression are triggered by withdrawal from other GABA-modulatory compounds, such as ethanol and BDZ, suggesting a common mechanism. Other studies have reported puberty or estrous cycle-associated increases in δ-GABAR, the most sensitive target of these steroids which underlies a tonic inhibitory current. In the studies reported here, the effect of steroids on inhibition, which influence anxiety state and seizure susceptibility, depend not only on the subunit composition of the receptor but also on the direction of Cl -current generated by these target receptors. The effect of neurosteroids on GABAR function thus results in behavioral outcomes relevant for pubertal mood swings, premenstrual dysphoric disorder and catamenial epilepsy, which are due to fluctuations in endogenous steroids.

Influence of the estrous cycle on some non reproductive behaviors and on brain mechanisms in the female rat

“…It has been proposed that ALLO, rather than P4 itself would be responsible of the action on the GABA system. Circulating levels of ALLO parallel those of P4 across the estrous cycle (see Smith et al, 2007). It is known that both P4 and ALLO have anxiolytic properties (Mora, Dussaubat, & Díaz-Véliz, 1996;Laconi, Casteller, Gargiulo, Bregonzio, & Cabrera, 2001).…”

“…In rats the granulosa cells of the ovary secrete P4 at high levels on P prior to ovulation and following the peak levels of E2, under both FSH and LH stimulation (see Smith, Shen, Gong, & Zhou, 2007). The highest steroid levels occur in the afternoon of P, when circulating levels of P4 and its metabolite allopregnenolone (ALLO) are elevated for 10-12 h (see Smith et al, 2007).…”

“…The highest steroid levels occur in the afternoon of P, when circulating levels of P4 and its metabolite allopregnenolone (ALLO) are elevated for 10-12 h (see Smith et al, 2007). Ovulation takes place on the night of P, and the resulting corpora lutea produces a secondary increase in P4 (and ALLO) on the day of D1 and lasting until the morning of D2 (see Smith et al, 2007). A P4 peak level occurs in the morning of D1 and in the evening of P (Figueiredo, Dolgas, & Herman, 2002).…”

“…P exhibits the highest peak levels of the anxiolytic P4 (and ALLO), the anti-stress PRL, and the controversial E2. This anxiolytic effect has been correlated with increased circulating levels of endogenous ALLO on P, and can be prevented by blockage of ALLO synthesis (see Smith at al., 2007). However, low levels of anxiety have also been described during P morning, when plasma P4 is at its lowest level, prior to the preovulatory surge (see Lovick, 2006).…”

“…The midbrain PAG plays a major role in mediating panic responses (see Smith et al, 2007). The GABAergic tone on the output neurons in the PAG is reduced during late D (D2), lowering the threshold for activation of the panic circuitry (see Lovick, 2006).…”