Effects of estradiol and estrogen receptor agonists on memory and neural function in rats.

摘要

Memory loss often coincides with the decline in circulating estrogens in women at menopause. Estradiol (E2) enhances memory in a variety of, but not all, cognitive tasks and treatment paradigms in ovariectomized (OVX) rats. However, effects on object recognition (OR) and object placement (OP) memory tasks in both subchronic (days) and acute (hours) treatment paradigms are unknown. Effects of estradiol were investigated on recognition memory using OR (nonspatial) and OP (spatial) memory tasks. Objects were explored in the sample trial (T1), and discrimination between sample (old) and new object/location in the recognition trial (T2) was examined. Estrogen enhanced performance in both treatment paradigms.; Mechanisms for estrogen's cognitive effects have not been resolved. To determine whether estrogen receptor alpha or beta (ERalpha, ERbeta) may mediate the role of E2 on cognition, effects of ERalpha-selective agonist, propyl pyrazole triol (PPT) and ERbeta-selective agonists, diarylpropionitrile (DPN) and Compound 19 (C-19) were examined in OVX rats using OR and OP. Subchronic and acute treatments with DPN and C-19, but not PPT, enhanced performance. Thus, memory enhancing effects of estrogen may by mediated by ERbeta. None or few effects of the hormone/agonists were found on elevated plus maze and open field; thus estrogenic effects on locomotion and anxiety could not account for the mnemonic effects.; Finally, DPN effects on levels of monoamines and metabolites using HPLC with electrochemical detection were investigated. Subchronic DPN increased dopamine levels, metabolites and activity in prefrontal cortex (PFC), whereas activity was decreased in the dentate gyrus and vertical limb of the diagonal band (VDB). Noradrenergic activity was increased in ventral hippocampus and PFC and decreased in CA1 and VDB. DPN also increased serotonin metabolite level in CA3 and PFC.; In conclusion, results suggest that the cognitive properties of estradiol may be mediated by the classical ERbeta, whereas the rapid, acute memory enhancements may be mediated by an ERbeta isoform, possibly on the membrane. Finally, increases and decreases in monoaminergic activity by DPN suggest that estradiol/agonists may mediate cognitive effects, in part, by modulating the activity of monoaminergic neurons. In addition, ERbeta agonists may be valuable for menopausal treatments.