Steroid hormone-mediated regulation of serotonin 5-HT 1A receptors in the aging hippocampus.

摘要

The aging process and steroid hormones estrogen and corticosterone alter hippocampal 5-HT_1A receptors. However, the ability of estrogen or corticosterone to regulate hippocampal 5-HT_1A receptors with advancing age is relatively unknown. The goal of these studies was to evaluate estrogen and corticosterone regulation of hippocampal 5-HT_1A receptor function throughout the lifespan of female Fischer 344 rats. The overall hypothesis tested was that steroid hormone-mediated regulation of 5-HT_1A receptor function diminishes with advancing age.; Estrogen-mediated regulation of 5-HT_1A receptor function in the aging hippocampas were the focus of the initial experiments. Results from autoradiographic analyses demonstrated that the density of [35S]GTPγS binding following 5-HT_1A receptor activation is decreased in old placebo-treated rats compared to old estrogen-treated rats and compared to young and middle-aged placebo-treated rats. These data suggest that with advancing age and estrogen depletion, hippocampal 5-HT_1A receptor coupling efficiency is diminished and furthermore, that estrogen may be able to protect against this loss.; Corticosterone-mediated regulation of 5-HT_1A receptor function in the aging hippocampas were the focus of the next experiments. Results from autoradiographic analyses demonstrated that the density of hippocampal 5-HT _1A receptor binding sites is increased in old adrenalectomized (ADX) rats compared to all other groups. Results from immunoblot analyses demonstrated that hippocampal Gα_i−1/2 protein expression is not significantly different between all groups tested. Results from autoradiographic analyses demonstrated that the density of [35S]GTPγS binding following 5-HT_1A receptor activation is not altered with varying corticosterone concentrations or advancing age. However, the density of hippocampal 5-HT_1A receptor binding sites is increased in old ADX rats, suggesting that the total population of receptors in this group exhibit an overall diminished coupling efficiency.; The final set of experiments in this thesis, utilizing an aging animal model, evaluated the compartmentalization of brain 5-HT_1A receptors into lipid rafts with advancing age and corticosterone treatment. Results demonstrated a trend towards decreased compartmentalization of brain 5-HT _1A receptors into lipid rafts in old ADX rats compared to other groups. Overall, these studies demonstrated that the process of aging, in combination with altered steroid hormones, mediate regulation of hippocampal 5-HT _1A receptor function.