The present study examined the effect of estradiol on hypothalamic serotonin-1A (5-HT1A) receptor signaling in female rats. We first examined the time-course effects of a single injection of the 5-HT1A 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 βg/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-HT1A receptor signaling, we measured the levels of Gαi, Gαo and Gαz proteins, which couple 5-HT1A receptors to their effector enzymes, in two subregions of the hypothalamus. The levels of Gαz 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 Gαi2 and Gαi3 proteins in both hypothalamic regions but did not affect Gαi1 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 Gαi2,3 proteins.
All Science Journal Classification (ASJC) codes
- Endocrinology, Diabetes and Metabolism
- Endocrine and Autonomic Systems
- Cellular and Molecular Neuroscience