Effects of selective estrogen receptor modulators on allocentric working memory performance and on dendritic spines in medial prefrontal cortex pyramidal neurons of ovariectomized rats

Estradiol and some selective estrogen receptor modulators (SERMs) are neuroprotective in a variety of experimental models of neurodegeneration, reduce the inflammatory response of glial cells, reduce anxiety and depression, promote cognition and modulate synaptic plasticity in the hippocampus of rodents. In this study we have assessed whether estradiol and two SERMs currently used in clinics, tamoxifen and raloxifene, affect medial prefrontal cortex function and morphology. Rats were ovariectomized and six days later some animals received a subcutaneous injection of the estrogenic compounds. In a first experiment animals were treated with estradiol benzoate or sesame oil vehicle. In a second experiment animals received raloxifene, tamoxifen or dimethyl sulfoxide as vehicle. Twenty four hours after the pharmacological treatment, animals were challenged to solve an allocentric working memory paradigm in a “Y” maze. Twenty trials consisting of a study phase and a test phase were conducted according to a delayed match-to-sample procedure in a single one-day session. Animals that were not submitted to behavioral test were used for Golgi analysis of the prefrontal cortex. Rats treated with estradiol benzoate, tamoxifen or raloxifene performed better in the Y maze and showed a significant increase in the numerical density of dendritic spines in secondary apical dendrites of layer III pyramidal neurons from the prelimbic/infralimbic prefrontal cortex, compared to their respective control groups. These findings suggest that estradiol, tamoxifen and raloxifene improve prefrontal cortex-related cognitive performance and modulate prefrontal cortex morphology in ovariectomized rats. ► Estradiol treatment improves allocentric working memory in ovariectomized rats. ► Estradiol treatment increases dendritic spine density in ovariectomized rats. ► Tamoxifen improves allocentric working memory in ovariectomized rats. ► Raloxifene improves allocentric working memory in ovariectomized rats. ► Both tamoxifen and raloxifene increase spine density in ovariectomized rats.