Comparative behavioral characterization of the neuroactive steroids 3α-OH,5α-pregnan-20-one and 3α-OH,5β-pregnan-20-one in rodents

Abstract

Pregnan steroids have been shown to possess anesthetic, hypnotic, anticonvulsant and anxiolytic properties. In this study, two endogenous neuroactive steroid isomers, 3α-hydroxy-5α-pregnan-20-one (3α,5α-P) and 3α-hydroxy-5β-pregnan-20-one 3α,5β-P), were studied for differences in their pharmacological properties using behavioral assays. 3α,5α-P and 3α,5β-P were similar in their potencies and efficacies in blocking pentylenetetrazol-induced seizures in mice (ED₅₀: 3α,5α-P=2.8 mg/kg and 3α,5β-P=3.0 mg/kg). Similarly, both neuroactive steroids produced roto-rod deficits within the same range of potency (TD₅₀:3α,5α-P=18.8 mg/kg and 3α,5β-P=21.2 mg/kg). However, in animal models of anxiety, subtle differences were observed between the two isomers. In both the light/dark transition test and elevated plus-maze, 3α,5β-P was more efficacious than 3α,5α-P, though both compounds had similar potencies. In the Geller-Seifter test, 3α,5β-P was more potent and efficacious than 3α,5α-P. Neither compound had significant effects on unpunished responding within the dose range tested. Both compounds produced similar biphasic curves in the locomotor test. All together, the data indicate that 3α,5α-P and 3α,5β-P have similar anticonvulsant activity, but the 5β-isomer possesses more potent and efficacious anxiolytic properties than the 5α-isomer.