Animal models of anxiety and stress- induced behavior: Effects of neuroactive steroids

Behaviorally, γ-aminobutyric acid (GABA)-agonist neuroactive steroids now are recognized to possess especially potent anesthetic, hypnotic, anxiolytic, and anticonvulsant properties. It has been over 60 years since Hans Selye (1942)1 reported the sedative-anesthetic activity of the hormones progesterone and deoxycorticosterone, where of 75 steroids tested by i.p. administration in rodents, 5β-pregnanedione was the most active. This led to the introduction of hydroxydione sodium (21-hydroxy-5β-pregnane-3,20-dione sodium succinate) as the first steroidal anesthetic in 1955.2 However, it was Margarethe Holzbauer and her colleagues, from 1969 to 1985, who isolated and identified pregnenolone, progesterone, allopregnanolone (3α,5α-THP), epiallopregnanolone (3β,5α- THP), allopregnanedione (5α-DHP), 20α-dihydroprogesterone, and allopregnanediol (5α-pregnane-3α,20α-diol) from ovarian venous blood of the rat, and measured the ovarian content and secretion rates of these steroids during proestrus (reviewed in Holzbauer3). Their work was seminal, but often is forgotten. Holzbauer and colleagues4 further demonstrated the in vivo secretion of pregnenolone, progesterone, and 3α,5α-THP by the adrenal gland of the rat in quantities similar to those secreted by the ovary in estrus.