D. Bitran et al., ANXIOLYTIC EFFECT OF PROGESTERONE IS ASSOCIATED WITH INCREASES IN CORTICAL ALLOPREGNANOLONE AND GABA(A) RECEPTOR FUNCTION, Pharmacology, biochemistry and behavior, 45(2), 1993, pp. 423-428
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.