Prolonged intracerebroventricular infusion of neurosteroids affects cognitive performances in the mouse

The effects of prolonged intracerebroventricular (i.c.v.) steroid infusions on memory performances (Y-maze arm discrimination test) and on neurosteroids brain levels were studied in young adult male mice. The Y-maze test consisted of two trials separated by a time interval. In the first trial, one arm of the maze (subsequently called novel arm) was closed, and mice were allowed to visit the two accessible arms. After a short 2-h intertrial interval (ITI), control mice explored preferentially the novel arm, whereas with a longer 6-h ITI, they did not remember the location of the novel arm and performed at random level (33% of time spent in each arm). Using a 2-h ITI, allopregnanolone (THPROG, 0.5 and 1 ng/h) decreased memory performances to random level after 3 and 6 days of infusion. Conversely, with a 6-h ITI, pregnenolone sulfate (PREG S, 10, 50, and 100 ng/h) significantly increased memory performances after 3 days, but only the smallest dose was still effective after 6 days. THPROG infusion (1 ng/h) increased the forebrain concentration of 5alpha-dihydroprogesterone (DHPROG) and tended to increase its own level. PREG S administration (10 ng/h) increased its own concentration and tended to increase those of pregnenolone (PREG) and of further metabolites. In conclusion, the memory-enhancing effects of PREG S and the inhibitory ones of THPROG have been confirmed. A persistent, however moderate, increase of PREG S brain concentration might be of interest for the treatment of amnesic deficits.