Ovarian steroids modify the behavioral and neurochemical responses of the central benzodiazepine receptor.

The effect of ovarian steroids on the benzodiazepine receptor was assessed in the elevated plus-maze and, after restraint stress, in benzodiazepine receptor binding assays. Vehicle-treated proestrous rats displayed anxiolytic behavior, relative to diestrus or estrous rats. Anxiolytic behavior was observed after 1 or 2 mg/kg diazepam in diestrus and estrus. However, whereas 4 mg/kg increased open arm exploration in diestrus, a decrease in the same measure was found at estrus. At proestrus, a decrease in anxiolytic behavior was observed after 2 and 4 mg/kg. In ovariectomized vehicle-treated rats, restraint stress increased NaCl-induced potentiation of 3H-flunitrazepam binding in cortical and cerebellar, but not in hippocampal membranes. Estradiol benzoate (2 micrograms) prevented the potentiation of flunitrazepam binding by NaCl in nonstressed and stressed animals, whereas progesterone (0.5 mg) increased the NaCl-induced potentiation of flunitrazepam binding in both nonstressed and stressed animals. Combined estradiol benzoate and progesterone treatment produced effects that were intermediate to those seen after injection of either steroid alone. The potentiation of flunitrazepam binding by NaCl observed in vehicle-treated stressed or progesterone-treated nonstressed animals was mimicked in vitro by addition to reaction test tubes of the neuroactive metabolite of progesterone, 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone). These results point to a significant role of ovarian hormones in modifying the stress response of the benzodiazepine receptor.