Enhancing effects of estrogen on inhibitory avoidance performance may be in part independent of intracellular estrogen receptors in the hippocampus

Abstract

Estradiol (E 2) can have classical actions via intracellular estrogen receptors (ERs) in the dorsal hippocampus, as well as effects independent of ERs (‘non-genomic’ mechanisms). These experiments investigated whether E 2’s cognitive enhancing effects in the inhibitory avoidance task require actions at ERs in the dorsal hippocampus. Ovariectomized (ovx) rats were administered E 2 (s.c. or to the dorsal hippocampus), an E 2 conjugate (E 2:BSA), or vehicle and/or an ER antagonist, tamoxifen (10 mg/kg s.c.) or ICI 182,780 (10 μg intrahippocampally), or vehicle for 2 days prior to training (Day 3) and testing (Day 4) in the inhibitory avoidance task. Exp 1: crossover latencies in the inhibitory avoidance task were significantly increased in ovx rats with s.c. E 2 silastic capsules or s.c. injections of 1000 or 10 μg E 2 compared to vehicle-administered rats. Exp 2: bilateral inserts of E 2 to the dorsal hippocampus significantly increased crossover latencies compared to vehicle. Exp 3: s.c. tamoxifen, the ER antagonist, did not block the increased crossover latencies produced by 10 μg E 2 s.c. (compared to vehicle). Exp 4: s.c. tamoxifen did not block the increased crossover latencies produced by intrahippocampal E 2 (compared to vehicle). Exp 5: ICI 182,780 was unable to attenuate the increased crossover latencies produced by intrahippocampal E 2. Exp 6: E 2:BSA administered to the dorsal hippocampus significantly enhanced performance on the inhibitory avoidance task compared to control implants to the hippocampus. The ability of systemic and intrahippocampal E 2 to similarly enhance inhibitory avoidance performance suggests that actions of E 2 in the dorsal hippocampus are sufficient to enhance cognitive performance. Further, that neither tamoxifen nor ICI 182,780 blocked E 2’s enhancing effects on inhibitory avoidance and that E 2:BSA was able to enhance performance suggest that non-genomic mechanisms may in part mediate E 2’s cognitive enhancing performance in this task.