Short-term exposure to a neuroactive steroid increases α4 GABAA receptor subunit levels in association with increased anxiety in the famale rat

Previous work from this laboratory has demonstrated that withdrawal from the neuroactive steroid 3 alpha ,5 alpha -THP (3 alpha -hydroxy-5 alpha -pregnan-20-one) after 3-week exposure to its parent compound, progesterone (P), increases anxiety and produces benzodiazepine (BDZ) insensitivity in female rats. These events were linked to upregulation of the alpha4 subunit of the GABA(A) receptor (GABAR) in the hippocampus [Brain Res. 507 (1998) 91; Nature 392 (1998) 926; J. Neurosci. 18 (1998) 5275]. The present study investigates the role of shorter term hormone treatment on a4 subunit levels as well as relevant behavioral and pharmacological end-points related to GABAR function. After 2-3 days of P exposure, two- to threefold increases in a4 protein levels were observed, which declined to control values after 5-6 days of hormone exposure. This effect was due to the GAGA-modulatory metabolite of P, 3 alpha ,5 alpha -THP. alpha4 upregulation was inversely correlated with BDZ potentiation of GABA-gated current, assessed using whole cell patch clamp techniques on acutely isolated hippocampal pyramidal cells. A near total BDZ insensitivity was observed by 2-3 days of hormone exposure in association with the maximal increase in a4 levels. Up-regulation of the alpha4 GABAR subunit was also reflected by an increase in anxiety in the elevated plus maze. A significant decrease in open arm entries was observed after 72-h exposure to P, an effect which recovered by 6 days of P treatment. As demonstrated in vitro, a4 upregulation also resulted in a relative insensitivity to the anxiolytic actions of BDZ. These results suggest that short-term exposure to 3 alpha ,5 alpha -THP produces changes in GABAR subunit composition similar to those that occur after chronic exposure and withdrawal from the steroid. (C) 2001 Elsevier Science B.V. All rights reserved.