Estradiol and ERβ agonists enhance recognition memory, and DPN, an ERβ agonist, alters brain monoamines

Abstract

Effects of estradiol benzoate (EB), ERα-selective agonist, propyl pyrazole triol (PPT) and ERβ-selective agonists, diarylpropionitrile (DPN) and Compound 19 (C-19) on memory were investigated in OVX rats using object recognition (OR) and placement (OP) memory tasks. Treatments were acute (behavior 4 h later) or sub chronic (daily injections for 2 days with behavior 48 h later). Objects were explored in sample trials (T1), and discrimination between sample (old) and new object/location in recognition trials (T2) was examined after 2-4 h inter-trial delays. Subjects treated sub chronically with EB, DPN, and C-19, but not PPT, discriminated between old and new objects and objects in old and new locations, suggesting that, at these doses and duration of treatments, estrogenic interactions with ERβ contributes to enhancements in recognition memory. Acute injections of DPN, but not PPT, immediately after T1, also enhanced discrimination for both tasks (C19 was not investigated). Effects of EB, DPN and PPT on anxiety and locomotion, measured on elevated plus maze and open field, did not appear to account for the mnemonic enhancements. Monoamines and metabolites were measured following DPN treatment in subjects that did not receive behavioral testing. DPN was associated with alterations in monoamines in several brain areas: indexed by the metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), or the MHPG/norepinephrine (NE) ratio, NE activity was increased by 60-130% in the prefrontal cortex (PFC) and ventral hippocampus, and NE activity was decreased by 40-80% in the v. diagonal bands and CA1. Levels of the dopamine (DA) metabolite, homovanillic acid (HVA), increased 100% in the PFC and decreased by 50% in the dentate gyrus following DPN treatment. The metabolite of serotonin, 5-hydroxyindole acetic acid (5-HIAA), was increased in the PFC and CA3, by approximately 20%. No monoaminergic changes were noted in striatum or medial septum. Results suggest that ERβ mediates sub chronic and acute effects of estrogens on recognition memory and that memory enhancements by DPN may occur, in part, through alterations in monoaminergic containing systems primarily in PFC and hippocampus.

High estradiol levels improve false memory rates and meta-memory in highly schizotypal women

“…While the effect of estradiol on false memories has not yet been directly examined in humans, recent animal studies have demonstrated improved object recognition memory in rats following estradiol treatment (e.g. Frye et al, 2007;Inagaki et al, 2010;Jacome et al, 2010). In contrast to previous studies investigating recognition performance, the present findings suggest that estradiol does not improve false recognition in humans in general.…”

Estrogen receptor (ER) subtype agonists alter monoamine levels in the female rat brain

“…Our previous work demonstrated that long-term treatment with E increases NE in the CA3 region of the hippocampus [49]. We have evidence to suggest that the commercially available ER␤ agonist diarylpropionitrile (DPN) also affects noradrenergic parameters in different regions of the hippocampus [50]. The present findings extend these observations by demonstrating Fig.…”

“…The fact that the ER␤ ligand had no effect on uterine or body weight but affected levels of neurotransmitters supports the idea that the dose was sufficient to selectively activate the ER␤. In addition, we have recent data to suggest that C19 improves performance in specific memory tasks similar to the ER␤ agonist, DPN [50]. Importantly, the data reflect only one time point and, as mentioned previously, at least some of the effects of E on monoamines are time-dependent [52].…”

Estradiol responsiveness of synaptopodin in hippocampal neurons is mediated by estrogen receptor β

“…This suggests that at least some of the effects of estradiol on cognition and behavior may be mediated by ER␤, and recent data point to a crucial role of ER␤ in estrogen-induced learning and memory. In fact, learning ability of ovariectomized ER␤-KO mice was impaired compared to that of WT ovariectomized females, strongly suggesting that ER␤ is required for optimal spatial learning [49,50]. Other studies focussed on anxiety-related behavior.…”