ANXIOLYTIC EFFECT OF PROGESTERONE IS ASSOCIATED WITH INCREASES IN CORTICAL ALLOPREGNANOLONE AND GABA(A) RECEPTOR FUNCTION

The effects of a SC injection of progesterone (0, 1, or 4 mg) on locom otor behavior and exploration of an elevated plus-maze were examined i n ovariectomized rats. At the completion of the behavioral tests, bloo d serum and cerebral cortical level of the 3alpha-hydroxy ring-A metab olite of progesterone, 3alpha-hydroxy-5alpha-pregnan-20-one (allopregn anolone), was also assessed. GABA-stimulated Cl-36- influx was studied in cortical synaptoneurosomes from a subgroup of ovariectomized femal es treated with vehicle or 4 mg progesterone. Whereas progesterone tre atment did not affect ambulation in a novel arena, significant anxioly tic behavior was detected in the plus-maze 4 h after administration of 1 or 4 mg progesterone. A dose-dependent increase in allopregnanolone level was found in serum and cortical homogenates. Studies of GABA-st imulated Cl- influx demonstrated that progesterone treatment increased the sensitivity of cortical synaptoneurosomes to GABA (i.e., decrease d the EC50) and increased the maximal efficacy with which GABA stimula ted Cl- transport (i.e., increased the E(max)). Together, these data s upport the hypothesis that the psychotropic effects observed after pro gesterone administration are due to the bioconversion of progesterone to allopregnanolone, which subsequently augments GABA(A) receptor-medi ated function.