Rapid Anxiolytic Activity of Progesterone and Pregnanolone in Male Rats

The effect of different doses of progesterone (1.0, 3.0, 10.0, 30.0, and 100.0 mg/kg) and pregnanolone (1.0, 3.0, 10.0, and 30.0 mg/kg) upon burying defensive and elevated plus-maze (EPM) tests was investigated in adult male rats and compared with the effects of diazepam (0.25. 0.50, 1.0, and 2.0 mg/kg). All drugs were suspended in a 0.2% methylcellulose solution and administered intraperitoneally 30 min prior to testing. Progesterone and pregnanolone were found to produce anxiolytic-like effects similar to those of diazepam. Thus, at certain doses, both drugs significantly increased the latency for burying and decreased the cumulative burying behavior, without modifying the number of shocks, and increased the time spent in the open arms of the maze, without affecting the spontaneous locomotor activity. These data clearly demonstrate that the defensive burying paradigm is useful to detect the anxiolytic-like properties of pregnanolone. An important finding was that progesterone produces significant behavioral effects 30 min after its administration. This finding suggests a rapid bioconversion of progesterone to its active ring-A reduced metabolites; however, the possibility remains that rapid behavioral effects of progesterone are due to a direct interaction with specific steroid receptors located on the plasma membrane, independently from the gamma-aminobutyric acid(A) (GABA(A)) receptor complex modulation.