ERβ-selective SERMs produce mnemonic-enhancing effects in the inhibitory avoidance and water maze tasks

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Abstract

Estradiol (17β-E2) can have mnemonic-enhancing effects; however, its mechanisms for these effects are not well-understood. The present studies examined effects of 17β-E2 and selective estrogen receptor modulators (SERMs) on emotional and spatial memory of female, Long-Evans rats. First, whether or not 17β-E2 has dose-dependent effects on inhibitory avoidance memory was investigated. Only the highest concentration of 17β-E2 examined (10 μg), which produces physiological concentrations of E2, was effective at enhancing inhibitory avoidance memory (Experiment 1). Further studies were designed to elucidate whether SERMs may produce mnemonic effects similar to those of 17β-E2. Compounds utilized were, the ERα-selective SERMs, propyl pyrazole triol (PPT) or 17α-E2, the ERβ-specific SERMs, diarylpropionitrile (DPN) or 7,12-dihydrocoumestan (coumestrol), or vehicle (oil). Post-training administration of 10 μg 17β-E2 or coumestrol enhanced memory in the inhibitory avoidance task compared to vehicle (Experiment 2). Memory in the water maze was enhanced by post-training administration of 17β-E2, coumestrol, or DPN, compared to vehicle (Experiment 3). Co-administration of 17α-E2&DPN enhanced inhibitory avoidance memory similar to that seen following 17β-E2 or coumestrol (Experiment 4). Administration of E2 2 h post-training was not effective at enhancing memory in the inhibitory avoidance or water maze tasks (Experiment 5). Lordosis of rats was enhanced by 17β-E2, 17α-E2, or PPT, compared to vehicle (Experiment 6). These data suggest that: E2’s actions at ERβ, rather than ERα, may enhance spatial memory, E2’s actions at ERα can facilitate sexual behavior, and that E2’s actions involving both ERα and ERβ may be important for emotional memory.

Introduction

Estradiol (E2) can enhance cognitive performance in some situations. Some menopausal women receiving E2 therapy have improved memory and logical reasoning compared to women not receiving E2 (Sherwin, 2000). However, not all studies report enhancing effects of hormone therapy among women. Recent clinical trials that were stopped due to adverse effects of hormone therapy reported negative effects of conjugated equine estrogen (CEE) and medroxyprogesterone on cognition (Shumaker et al., 2003). For example, women taking CEE alone showed a greater risk for dementia and global cognitive decline, particularly among women with lower cognitive abilities at the initiation of treatment (Espeland et al., 2004, Shumaker et al., 2004). E2’s variable effects on cognitive processes may be due in part to hormone regimen utilized, prior exposure to E2, and the nature of the cognitive task investigated. Indeed, it has been proposed that disparate hormone levels produced by various hormone therapy regimen may influence whether E2 has negative or positive effects on cognition (Hogervorst et al., 2000, Linzmayer et al., 2001).

E2 also has variable effects on learning and memory in animal models, which may be a result of different effects of E2 at training and/or testing. For example, performance of rodents in behavioral estrus, which have high endogenous E2 levels, has been reported to be better, worse, or unchanged compared to that seen in other phases of the cycle, when E2 is lower (Berry et al., 1997, Frye, 1995, Galea et al., 1995, Korol et al., 2004, Stackman et al., 1997, Warren and Juraska, 1997). Further, when E2—replacement occurs pre-training, there are also discrepant effects on performance (Chesler and Juraska, 2000, Foster et al., 2003, Marriott et al., 2002, Marriott and Korol, 2003). Given that E2 can have profound effects on activity and arousal (Morgan and Pfaff, 2001, Morgan et al., 2004, Ogawa et al., 2003), the presence of E2 during training may alter activity and/or arousal, thereby influencing performance and/or consolidation of information. In support, post-training E2 administration generally has more consistent mnemonic effects. E2 administered immediately post-training enhances memory in the object recognition, water maze, and inhibitory avoidance tasks (Luine et al., 2003, Packard and Teather, 1997, Rhodes and Frye, 2004). These data, together with clinical reports, suggest that E2-enhanced learning may depend upon E2 regimen and task examined.

E2 can have enhancing effects on performance and memory in learning tasks that require different cognitive processes. For example, E2 can enhance multiple types of spatial memory. Both reference and working memory is improved with administration of E2 (El-Bakri et al., 2004, Heikkinen et al., 2002, Heikkinen et al., 2004, Lacreuse and Herndon, 2003, Luine et al., 2003). Emotional learning is also enhanced with E2. Chronic or low-dose E2 regimen to ovx rodents enhances contextual and cued fear conditioning (Garey et al., 2001, Jasnow et al., 2005). Acute or chronic E2 regimen that result in physiological levels of E2 enhance memory in the inhibitory avoidance task (Frye and Rhodes, 2002, Rhodes and Frye, 2004). Thus, E2 has positive mnemonic effects in learning tasks that involve different parameters.

E2 has multiple mechanisms of action, including actions at intracellular ERs, which may contribute to its variable mnemonic effects. Notably, two ER isoforms have been characterized, ERα and ERβ, both of which have been localized to the hippocampus (Shughrue, Lane, & Merchenthaler, 1997). The two ER isoforms may have discrepant effects on various types of cognitive processes. In support, female rats fed a diet rich in the ERβ-selective phyotestrogen, genestein, perform better in the radial arm maze than do rats on a phytyoestrogen-free diet (Lephart et al., 2002). In contrast, 17β-E2 or selective ER modulators (SERMs), which bind with greater avidity to ERα, such as, 17α-E2 or 16α-iodo-E2, to rats enhances object recognition compared to vehicle (Luine et al., 2003). Notably, this task requires a high level of exploration. Other processes that require increased exploration, such as sexual behavior, also involve actions at ERα (Morgan et al., 2004). Thus, actions at ERβ may mediate spatial learning, whereas ERα may mediate exploratory behaviors.

The present studies examined whether selective actions at ERs are involved in different aspects of learning. We hypothesized that if ERβ mediates spatial learning and ERα modulates arousal, then ERβ-selective SERMs should enhance water maze learning (spatial learning task) and ERα-selective SERMs should enhance inhibitory avoidance (emotional learning task) and sexual behavior of ovariectomized (ovx) female rats.

Section snippets

Materials and methods

All methods in the present experiments were conducted with the approval of the Institutional Animal Care and Use Committee of SUNY-Albany.

Experiment 1

Cross-over latencies were significantly different among groups (H(4,5) = 10.44, P < 0.05). Rats administered 10 μg 17β-E2 had significantly longer latencies to cross-over to the shock-associated side of the chamber compared to rats administered 0, 1, 2, or 5 μg 17β-E2 (see Fig. 1).

Experiment 2

Cross-over latencies in the inhibitory avoidance task were significantly different among groups administered SERMs (H(5,6) = 25.93, P < 0.01). Rats administered 17β-E2 or coumestrol had significantly longer cross-over latencies

Discussion

The present data supported our hypothesis that actions at ERβ enhance spatial memory in the water maze task, that ERα activity modulates sex behavior, and that emotional memory may be mediated by actions at both ERα and ERβ. First, administration of 17β-E2, DPN, or coumestrol significantly decreased latencies to find the hidden platform in the water maze task compared to vehicle. Second, 17β-E2, PPT, and 17α-E2, but not DPN or coumestrol, enhanced sexual behavior of rats compared to vehicle.

Acknowledgments

This research was supported by grants from The National Science Foundation (IBN 03-16083 and 04-35009). The technical assistance of Rebecca Habernig is appreciated.

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