Estrogens Act in Rat Hippocampus and Frontal Cortex to Produce Rapid, Receptor-Mediated Decreases in Serotonin 5-HT_1A Receptor Function

Abstract

Previously our laboratory has shown that 17β-estradiol in vivo rapidly decreases R(+)-8-OH-DPAT-stimulated [³⁵S]GTPγS binding (a measure of the initial biochemical event in the intracellular signaling pathway associated with 5-HT_1A receptors) in the hippocampus, frontal cortex and amygdala. Studies were designed to determine if 17β-estradiol also acts in vitro on estrogen receptors in the hippocampus and frontal cortex to decrease 5-HT_1A receptor function. Hippocampus and frontal cortex were dissected from ovariectomized rats and incubated for up to 3 h with various estrogens and antiestrogens; membrane homogenates were prepared for R(+)-8-OH-DPAT-stimulated [³⁵S]GTPγS binding assays. 17β-Estradiol (10^–6 M) decreased the maximal response in the R(+)-8-OH-DPAT-stimulated [³⁵S]GTPγS binding assay in a time-dependent manner (observed at 30, 60 and 120 min) in both hippocampus and frontal cortex. The hormone, however, did not alter the EC₅₀ of R(+)-8-OH-DPAT. When hippocampus and frontal cortex were incubated in graded concentrations of 17β-estradiol for 1 h, the calculated EC₅₀ was approximately 2.5 × 10^–8 M in both brain regions. The nonestradiol estrogen diethylstilbestrol also decreased 5-HT_1A receptor function while the less potent estrogens 17α-estradiol and estriol were inactive at 5 × 10^–8 M. The estrogen receptor antagonist ICI 182,780 potently and completely blocked the effects of 17β-estradiol on 5-HT_1A receptor function with an apparent K_B of approximately 10^–9 M. These data demonstrate clearly that estrogens can act on estrogen receptors located in hippocampus and frontal cortex of ovariectomized rats to produce rapid heterologous decreases in 5-HT_1A receptor function.

Estrogen Prevents 5-HT1A Receptor-Induced Disruptions of Prepulse Inhibition in Healthy Women

“…The most likely mechanism responsible for the observed PPI effects is that estrogen treatment altered signalling of the 5-HT 1A receptor. Acute estrogen treatment in ovariectomized rats desensitized 5-HT 1A receptor function, as indicated by a reduction in [ 35 S]GTPgS binding (Mize and Alper, 2000;Mize et al, 2001). Further studies are required to investigate if similar mechanisms occur in humans.…”

Participation of the 5-HT1A Receptor in the Antidepressant-Like Effect of Estrogens in the Forced Swimming Test

“…Therefore, it can be concluded that the 5-HT 1A receptor subtype is a mediator of the antidepressant-like action of E 2 . Evidences in favor of this hypothesis are the results derived from in vitro and in vivo studies, showing that the 5-HT 1A receptor subtype is a target of estrogens and some estrogen-like compounds (Bethea et al, 1998;Biegon et al, 1983;Mize and Alper, 2000;Mize et al, 2001;Raap et al, 2000;Uphouse, 2000). Indeed, Lu and Bethea (2002) demonstrated that E 2 induces the desensitization of 5-HT 1A receptors in the DRN of monkeys.…”

Rapid Uncoupling of Serotonin-1A Receptors in Rat Hippocampus by 17β-Estradiol in vitro Requires Protein Kinases A and C

“…We have recently shown that in vitro, 17β-estradiol and diethylstilbestrol decrease 5-HT 1A receptor coupling to Gα in rat hippocampus and frontal cortex [13]. In addition, we demonstrated that the effects of 17β-estradiol are potently and completely blocked by the estrogen receptor antagonist ICI 182,780.…”

“…A piece of tissue was placed into one well of a 6-well cell culture plate along with 10 ml of HEPES buffer containing vehicle, 17β-estradiol or related compound. The plates were transferred to a water bath (37°C) under continuous aeration [13]. In studies involving estrogen receptor antagonists or protein kinase inhibitors, a 15-min preincubation in the presence of the inhibitor was performed prior to the addition of 17β-estradiol.…”