Effect of Perinatal Blockade of Androgen Receptors on Estrogen Receptor‐Levels in Specific Brain Regions and Spatial Working Memory in Male Rats

Abstract

Sex differentiation of the male rat brain occurs during the perinatal period (four days prior to and four days after birth) in the presence of testosterone (TS) which serves as a prehormone and gets metabolized to either 17β‐estradiol (E2) or dihydrotestosterone (DHT). E2 exerts its effect by binding to estrogen receptor (ER‐ and ER‐β) and DHT to androgen receptor (AR). Both ER and AR are shown to be important in the sexual differentiation of the brain. ER‐ is expressed in the hypothalamus, amygdala, and hippocampus in greater amounts and is associated with memory and sexual behavior. Whether blockade of AR during the perinatal period modulates the concentrations of ER‐ in the adult brain and, in turn, affects spatial working memory (SWM) was tested in this study. Two timed‐pregnant Long Evans rats were administered Flutamide (20mg/kg; SC) or vehicle during the last four days of pregnancy. Ten mg/kg (SC) of flutamide or vehicle was given to the newborn male pups for an additional four days. We tested SWM in these male rats when they reached postnatal day 65 and found that flutamide treatment improved SWM compared to control animals. At the end of the behavioral study, these animals were sacrificed and trunk blood was collected to measure serum E2 and TS levels. We found that the behavioral changes were associated with elevated serum E2 and reduced TS levels. The hypothalamus, amygdala, and hippocampus were isolated from the frozen brain tissue and ER‐ protein levels were measured using chemiluminescent western blots. Flutamide‐treated group showed an increase in ER‐ levels in the hypothalamus and the amygdala whereas concentrations in the hippocampus was decreased. Our results suggest that the increased ER‐ levels in the hypothalamus and amygdala along with increased serum E2 levels appear to improve SWM.