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

• Published in: Psychopharmacology Vol. 118; no. 1; p. 65
• Main Authors: Wieland, S, Belluzzi, J D, Stein, L, Lan, N C
• Format: Journal Article
• Language: English
• Published: Germany 01.03.1995
• Subjects: Animals; Anti-Anxiety Agents - pharmacology; Behavior, Animal - drug effects; Conflict (Psychology); Dose-Response Relationship, Drug; Hypnotics and Sedatives - pharmacology; Isomerism; Male; Mice; Mice, Inbred Strains; Motor Activity - drug effects; Pentylenetetrazole; Postural Balance - drug effects; Pregnanolone - pharmacology; Rats; Rats, Sprague-Dawley; Seizures - chemically induced; Seizures - prevention & control
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/BF02245251

Pregnan steroids have been shown to possess anesthetic, hypnotic, anticonvulsant and anxiolytic properties. In this study, two endogenous neuroactive steroid isomers, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) and 3 alpha-hydroxy-5 beta-pregnan-20-one 3 alpha,5 beta-P), were studied for differences in their pharmacological properties using behavioral assays. 3 alpha,5 alpha-P and 3 alpha,5 beta-P were similar in their potencies and efficacies in blocking pentylenetetrazol-induced seizures in mice (ED50: 3 alpha, 5 alpha-P = 2.8 mg/kg and 3 alpha,5 beta-P = 3.0 mg/kg). Similarly, both neuroactive steroids produced roto-rod deficits within the same range of potency (TD50: 3 alpha,5 alpha-P = 18.8 mg/kg and 3 alpha,5 beta-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, 3 alpha,5 beta-P was more efficacious than 3 alpha,5 alpha-P, though both compounds had similar potencies. In the Geller-Seifter test, 3 alpha,5 beta-P was more potent and efficacious than 3 alpha,5 alpha-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 3 alpha,5 alpha-P and 3 alpha,5 beta-P have similar anticonvulsant activity, but the 5 beta-isomer possesses more potent and efficacious anxiolytic properties than the 5 alpha-isomer.