GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid

Abstract

The hormone progesterone is readily converted to 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alpha-THP) in the brains of males and females. In the brain, 3alpha,5alpha-THP acts like a sedative, decreasing anxiety and reducing seizure activity, by enhancing the function of GABA (gamma-aminobutyric acid), the brain's major inhibitory neurotransmitter. Symptoms of premenstrual syndrome (PMS), such as anxiety and seizure susceptibility, are associated with sharp declines in circulating levels of progesterone and, consequently, of levels of 3alpha,5alpha-THP in the brain. Abrupt discontinuation of use of sedatives such as benzodiazepines and ethanol can also produce PMS-like withdrawal symptoms. Here we report a progesterone-withdrawal paradigm, designed to mimic PMS and post-partum syndrome in a rat model. In this model, withdrawal of progesterone leads to increased seizure susceptibility and insensitivity to benzodiazepine sedatives through an effect on gene transcription. Specifically, this effect was due to reduced levels of 3alpha,5alpha-THP which enhance transcription of the gene encoding the alpha4 subunit of the GABA(A) receptor. We also find that increased susceptibility to seizure after progesferone withdrawal is due to a sixfold decrease in the decay time for GABA currents and consequent decreased inhibitory function. Blockade of the alpha4 gene transcript prevents these withdrawal properties. PMS symptoms may therefore be attributable, in part, to alterations in expression of GABA(A) receptor subunits as a result of progesterone withdrawal.

Effect of the α subunit subtype on the macroscopic kinetic properties of recombinant GABAA receptors

“…Our results showing that the α4 subtype confers a very rapid deactivation rate are also consistent with several neuronal studies in which pathological conditions of hyperexcitability cause an increase in the relative expression of the α4 subunit and a more rapid IPSC decay rate (Smith et al, 1998;Follesa et al, 2004). Again, the change in kinetic properties could be prevented by reducing expression of the α4 subunit (Smith et al, 1998).…”

“…This pattern is observed in models of hyperexcitability, in which faster IPSC decay rates are associated with an increased seizure susceptibility (Smith et al, 1998). The increase in seizure activity could be reduced by decreasing α4 subunit expression (Smith et al, 1998) or by increasing α1 subunit expression (Raol et al, 2006). Our results suggest that either of these changes in subunit expression would slow the deactivation rate.…”

“…Shifts in expression from isoforms with slower deactivation rates to faster rates would be expected to lead to less effective GABAergic neurotransmission, and likely reduced inhibitory tone. This pattern is observed in models of hyperexcitability, in which faster IPSC decay rates are associated with an increased seizure susceptibility (Smith et al, 1998). The increase in seizure activity could be reduced by decreasing α4 subunit expression (Smith et al, 1998) or by increasing α1 subunit expression (Raol et al, 2006).…”

Neurosteroids in the context of stress: Implications for depressive disorders

“…The work of Smith and her colleagues has demonstrated that neurosteroid withdrawal results in a state of anxiety and to a relative insensitivity to the anxiolytic effects of benzodiazepines and that these effects appear to be mediated by an increase in the expression of the α4-containing GABA A receptor subunit in brain (Smith et al, 1998a(Smith et al, , 1998b(Smith et al, , 2006. Recently, Smith et al (2006), examined withdrawal from naturally occurring high nocturnal concentrations of allopregnanolone in mice via the administration of finasteride for 3 days.…”

Progesterone selectively increases amygdala reactivity in women

“…[11][12][13] This neurosteroid potentiates the inhibitory actions of g-aminobutyric acid (GABA) by modulation of the GABA A receptor. 14 Consistent with this GABAergic mechanism, progesterone and allopregnanolone administration usually produce an anxiolytic effect 11,13 by the action on the amygdala.…”