SELECTIVE ESTROGEN RECEPTOR MODULATORS AND COGNITION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Selective estrogen receptor modulators (SERMs) are used to address life-threatening clinical problems but the effects of SERMS on cognition are not known. We therefore used the rhesus monkey model to determine the effects of estradiol benzoate (EB), and the SERMs tamoxifen, DPN (a selective ER-beta agonist), and PPT (a selective ER-alpha agonist) on cognitive function. Animals were tested on a battery of cognitive tests that are presumed to be sensitive to sex hormones or ovarian status. Twenty-two monkeys were given memory and cognitive tasks including Delayed Non-Matching-To-Sample (DNMS) with mixed delays (1, 10 and 30s), and the object, face, and spatial versions of the Delayed Recognition Span Test (DRST). Following a baseline period, monkeys were randomly assigned to one of 3 treatment groups: estradiol benzoate (EB), selective ER-beta agonist (DPN) or selective ER modulator tamoxifen (TAM). In each treatment group, monkeys received oil vehicle for 2 weeks and the drug for 2 weeks, in a cross-over design. After a 4-week washout, a subset of 7 monkeys was re-tested on the battery for 2 weeks with oil vehicle and 2 weeks with a selective ER-alpha agonist (PPT). Overall, drug treatments had modest effects on performance. EB treatment, compared to placebo, was associated with better scores on the DNMS-mixed delays and faster response times at the 10 and 30s delays. Other tasks were unaffected by EB treatment. Monkeys treated with PPT had shorter response times on DNMS-mixed delays. Monkeys with TAM obtained relatively better scores at 30s delay and lower scores at 1s delay, and had increased response times with longer delays. DPN had no effect either on scores or response times on DNMS, but did result in increased response times on the DRST tasks. Overall, these results suggest that estrogen receptor specificity must be considered in evaluating endocrine effects on cognition.