Estrogen Reduces Serotonin-1A Receptor-Mediated Oxytocin Release and Gα_i/o/z Proteins in the Hypothalamus of Ovariectomized Rats

Abstract

The present study examined the effect of estradiol on hypothalamic serotonin-1A (5-HT_1A) receptor signaling in female rats. We first examined the time-course effects of a single injection of the 5-HT_1A receptor agonist (±)8-OH-DPAT (5, 15 or 30 min prior to decapitation), and dose response of (+)8-OH-DPAT (50, 100, 200 or 500 µg/kg, s.c.) on plasma hormones in ovariectomized rats that received a daily injection of β-estradiol 3-benzoate (10 µg/day, s.c.) or vehicle (sesame oil) for 2 days. In vehicle- and estrogen-treated rats, the peak response of hormones occurred at 15 min after injection and the time-course of oxytocin and adrenocorticotropic hormone (ACTH) responses to an injection of 8-OH-DPAT were comparable. However, only the oxytocin response was reduced by estrogen treatment. A second experiment compared the ACTH and oxytocin responses with doses of 50 or 200 µg/kg, s.c. of (+)8-OH-DPAT vs. (±)8-OH-DPAT in ovariectomized rats that were treated with oil or β-estradiol 3-benzoate (10 µg/day, s.c.) for 2 days. (+)8-OH-DPAT and (±)8-OH-DPAT produced a similar magnitude of increase in plasma levels of ACTH and oxytocin. Treatment with β-estradiol 3-benzoate produced a significant and comparable reduction in the oxytocin response to the highest dose (200 µg/kg, s.c.) of both (+)8-OH-DPAT and (±)8-OH-DPAT but did not alter the ACTH response to either (+)8-OH-DPAT or (±)8-OH-DPAT. In the dose-response experiment, a dose of 50 µg/kg of (+)8-OH-DPAT produced a maximal increase in plasma levels of ACTH, while the maximal oxytocin response was achieved with a dose of 200 µg/kg, s.c. Treatment with β-estradiol 3-benzoate reduced the maximal oxytocin response to (+)8-OH-DPAT (by 29%) but did not alter the ACTH response to any doses of (+)8-OH-DPAT. To examine potential mechanisms mediating the effects of estrogen on 5-HT_1A receptor signaling, we measured the levels of Gα_i, Gα_oand Gα_zproteins, which couple 5-HT_1A receptors to their effector enzymes, in two subregions of the hypothalamus. The levels of Gα_z protein were reduced in the mediobasal hypothalamus (containing the ventromedial and arcuate nuclei), which mainly expresses estrogen receptor-α, but not in the paraventricular hypothalamus, which mainly expresses estrogen receptor-β. Estradiol reduced the levels of Gα_i2 and Gα_i3proteins in both hypothalamic regions but did not affect Gα_i1 levels in either area. Combined, the data suggest that racemic and stereoselective 8-OH-DPAT have similar neuroendocrine effects and that both estrogen receptor-α and estrogen receptor-β mediate the reduction in levels of Gα_i2,3 proteins.

Effects of Estrogen on the Serotonergic System and Calcitonin Gene-Related Peptide in Trigeminal Ganglia of Rats

“…Our results are in line with the finding that acute and chronic estrogen treatments increase 5-HT 2A receptor mRNA in the dorsal raphe nucleus in ovariectomized rats. 33,34 In contrast, it was observed that estrogen treatment resulted in a decrease in 5-HT 1A receptor gene expression and receptor function in the limbic region, cortex and dorsal raphe nucleus of rats 35,36 and nonhuman primates. 37,38 This may be due to dosage or route of administration dependent effect 39 of estrogen on the expression of 5-HT 1A receptors.…”

GPR30 is necessary for estradiol-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the rat hypothalamus

“…We previously reported that 2-day peripheral administration of EB resulted in the desensitization of 5-HT 1A receptor signaling in the rat PVN (D’Souza et al, 2004; Raap et al, 2000). Our previous study demonstrated that this desensitization is not mediated by ERβ, as treatment with a selective ERβ agonist, DPN, did not mimic the results of EB treatment.…”

Influence of Gender Difference in the Antidepressant Effect of Fluoxetine in Mice in Tail Suspension Test

“…Furthermore, the administration of estrogen upregulates 5-HT synthesizing enzyme, i.e. tryptophan hydroxylase [55,56], downregulates SERT upon shortterm treatment [57], whereas upregulates SERT following long-term treatment [58], decreases the expressions of 5-HT metabolizing enzyme, i.e., monoamine oxidase [59], and reduces the expression of 5-HT 1A receptor in the various regions of brain [60,61]. Therefore, estrogen modulates both the density of 5-HT receptors and 5-HT turnover [62,63].…”