Progesterone withdrawal increases the α4 subunit of the GABA_A receptor in male rats in association with anxiety and altered pharmacology - A comparison with female rats

Withdrawal from the neurosteroid 3α,5α-allopregnanolone after chronic administration of progesterone increases anxiety in female rats and up-regulates the α4 subunit of the GABA_A receptor (GABA_A-R) in the hippocampus. We investigated if these phenomena would also occur in male rats. Progesterone withdrawal (PWD) induced higher α4 subunit expression in the hippocampus of both male and female rats, in association with increased anxiety (assessed in the elevated plus maze) comparable to effects previously reported. Because α4-containing GABA_A-R are insensitive to the benzodiazepine (BDZ) lorazepam (LZM), and are positively modulated by flumazenil (FLU, a BDZ antagonist), we therefore tested the effects of these compounds following PWD. Using whole-cell patch clamp techniques, LZM-potentiation of GABA _(EC20)-gated current was markedly reduced in CA1 pyramidal cells of male rats undergoing PWD compared to controls, whereas FLU had no effect on GABA-gated current in control animals but increased it in PWD animals. Behaviorally, both male and female rats were significantly less sensitive to the anxiolytic effects of LZM. In contrast, FLU demonstrated significant anxiolytic effects following PWD. These data suggest that neurosteroid regulation of the α4 GABA_A-R subunit may be a relevant mechanism underlying anxiety disorders, and that this phenomenon is not sex-specific.