The beneficial effects of estradiol on attentional processes are dependent on timing of treatment initiation following ovariectomy in middle-aged rats

The goal of the present study was to explore the effects of long-term hormone deprivation on the ability of subsequent estrogen treatment to affect attention performance on the 5-choice serial reaction time task (5-CSRTT). In an initial experiment to assess estradiol effects in young adults, 2-month-old rats were trained on the 5-CSRTT, then ovariectomized and immediately implanted with capsules containing cholesterol (n=10) or estradiol (n=10). Then rats were tested on the 5-CSRTT under baseline task parameters, under increased task difficulty (behavior challenge condition), and finally in muscarinic and nicotinic drug challenge conditions. In a second experiment, 10-month-old rats were trained on the 5-CSRTT and at 12 or 17 months of age rats were ovariectomized and treated with estradiol or cholesterol, so that one group received continuous cholesterol control treatment, two groups received estradiol treatment immediately following ovariectomy (either at 12 or 17 months), and one group received delayed estradiol treatment initiated 5 months following ovariectomies. At 17 months of age, rats were tested on the 5-CSRTT. Baseline performance was comparable between estradiol- and cholesterol-treated rats of both age groups. However, young estradiol-treated rats outperformed controls when behavior was challenged by shortening the intertrial interval (Short ITI). In the same Short ITI condition, middle-aged rats receiving immediate estradiol treatment beginning at the age of 17 months, but not 12 months, outperformed controls as well as animals receiving delayed estradiol treatment. No differences between groups were found in the cholinergic drug challenge conditions. These data indicate that chronic estradiol treatment for approximately 1 month but not 6 months is able to enhance attention performance, and that prolonged ovarian hormone deprivation attenuates these beneficial effects of subsequent estradiol treatment. These findings have implications for informing clinical research about the importance of timing and duration of hormone treatment.