Steroid hormone withdrawal alters the GABA(A) receptor pharmacological profile: An electrophysiological study

The steroid hormone progesterone (P) is readily converted to 3alpha-OH-5alpha-pregnan-20-one (3alpha, 5alpha-THP) in the brains of males and females. 3alpha, 5alpha-THP, like benzodiazepines (BDZs), can mediate sedative effects to decrease anxiety and seizure susceptibility by potentiating the function of GABA, the major inhibitory neurotransmitter in the brain. Clinical symptoms of pre-menstrual syndrome (PMS) such as anxiety is strongly correlated with abrupt declines in circulating levels of P as well as its GABA-modulatory metabolite, 3alpha, 5alpha-THP. However, we understand little of the changes in GABAA receptor (GABA-R) pharmacology after P withdrawal.; One goal of this research was to characterize GABA-mediated function after P withdrawal using electrophysiological means. Towards this end, a multiple P-withdrawal paradigm was designed to mimic PMS and post-partum syndrome in a rat model. The hypothesis tested electrophysiologically was that withdrawal from elevated circulating levels of the female sex steroid P may change electrophysiological parameters of the GABA-R.; Twenty-four hours after removal of a three-week s.c. P capsule implant (24 hours P withdrawal), the pharmacological profile of GABA-R was changed; there was a 70--100% reduction in the ability of lorazepam (LZM), a BDZ agonist, to potentiate GABA-evoked Cl- current in acutely isolated hippocampal CA1 neurons. This effect was a result of withdrawal from 3alpha, 5alpha-THP rather than P, as blockade of 3alpha, 5alpha-THP formation with indomethacin during chronic P treatment prevented the BDZ insensitivity.; To test the hypothesis that decreases in total integrated GABA-gated current observed in the isolated CA1 pyramidal cells would be manifested as reduced GABA inhibition at the circuit level, the paired-pulse inhibition (PPI) paradigm was used to evaluate the GABA-R-mediated effects in hippocampal slices. In order to test the hypothesis that alpha4-subunit up-regulation may produce the observed changes in GABA-R pharmacology, antisense oligonucleotide administration was used to suppress expression of the alpha4 subunit of GABA-R induced by P withdrawal. The results indicate that treatment prevented most withdrawal effects such as LZM insensitivity, the altered pharmacological profile, the decreased PPI, and the decreased GABA current decay time constant in isolated neurons. (Abstract shortened by UMI.)...