Dehydroepiandrosterone and its sulfate enhance memory retention in mice

Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), major naturally occurring precursors of both androgenic and estrogenic steroids, were shown in the present study to have convincing memory enhancing effects in mice. Post-training intracerebroventricular (i.c.v.) administration of DHEA in dimethylsulfoxide (2 microliters) prevented the amnesia for footshock active avoidance training (FAAT) caused by the same volume of dimethylsulfoxide alone. DHEAS significantly enhanced retention of FAAT in weakly trained mice whether injected i.c.v. or s.c. immediately post-training or given in the drinking water for a 2-week period. In the latter instance DHEAS was shown to facilitate retention of FAAT without enhancing acquisition. The maximally effective doses were: i.c.v., 162 ng/mouse; s.c., 700 micrograms/mouse; and oral, 1.45 mg/mouse/day. DHEAS administered i.c.v. occluded the amnestic effects of anisomycin (inhibitor of protein synthesis) and scopolamine (muscarinic cholinergic antagonist). There was a time-dependence of the facilitatory effects of post-training i.c.v. administration of DHEAS on retention of FAAT, significant enhancement of retention being observed when it was given either immediately (within 2 min) or at 30 and 60 min after training, but not at 90 or 120 min. DHEAS given i.c.v. also improved retention for step-down passive avoidance. In all instances, dose-dependent inverted U curves were obtained in a manner typical for memory enhancing substances. At a practical level, these experiments open new possibilities for the development of substances that may help in alleviating amnesic disorders in man.