The most potent, naturally occurring estrogen, estradiol, is involved in the physiological control of food intake. Estradiol appears to exert its anorexigenic effect by activating nuclear estrogen receptors (ERs), which are expressed widely in peripheral tissues and in the brain. However, the relative contributions of peripheral and central ERs to estradiolís anorexigenic effect are largely unknown. Experiment 1 utilized an antiestrogenic compound that fails to cross the blood brain barrier, ICI 182,780 (ICI), to determine whether blockade of either peripheral or central ERs could attenuate the anorexigenic effect of estradiol in ovariectomized (OVX) rats. Peripheral ICI treatment failed to attenuate estradiolís anorexigenic effect at a dose that was sufficient to block a classic ER action in the periphery. In contrast, central ICI infusion blocked estradiolís anorexigenic effect, suggesting that activation of central, but not peripheral, ERs is necessary for estradiolís anorexigenic effect.
Estradiol appears to make rats more sensitive to the anorexigenic effects of serotonin (5-HT), a neurotransmitter that is released during meals and functions to inhibit meal size. For example, previous research from our lab revealed that estradiol increases the anorexigenic effects of fenfluramine (FEN), a serotonergic drug that produces a rapid increase in 5-HT neurotransmission. To begin to examine the mechanism by which estradiol increases the anorexigenic effects of 5-HT, Experiment 2 was designed to investigate whether estradiol increases the expression of serotonergic genes involved in the regulation of 5-HT neurotransmission, including pheochromocytoma 12 ETS domain transcription factor (Pet-1), 5-hydroxytryptophan transporter (5-HTT), and tryptophan-hydroxylase isoform 2 (TPH-2), in the midbrain raphe nuclei (dorsal and medial raphe nuclei) of OVX rats. Estradiol increased Pet-1, 5-HTT, and TPH-2 mRNA levels in midbrain raphe nuclei at a time that coincided with estradiolís inhibitory effect on food intake. These findings demonstrate that estradiol increases the expression of serotonergic genes in midbrain raphe nuclei and this effect may increase serotonergic tone in a feeding-related, neural circuit. The 5-HT agonist, FEN, increases 5-HT neurotransmission by increasing the release of 5-HT, by decreasing the reuptake of 5-HT, and by activating postsynaptic 5-HT2C receptors. Because of this lack of specificity, it is hard to determine whether estradiol may be acting presynaptically, to increase release of 5-HT, or postsynaptically, to increase activation of excitatory 5-HT2C receptors. Experiment 3 was designed to test the latter hypothesis. The anorexigenic effect of mCPP, a selective 5-HT2C receptor agonist, was examined in estradiol- and vehicle-treated OVX rats. In support of our hypothesis, the magnitude of mCPP-induced anorexia was significantly greater in estradiol-treated rats, relative to oil-treated rats. This finding suggests that estradiol interacts with the postsynaptic 5-HT2C receptor to decrease food intake. Together, these findings provide the first demonstrations that activation of central ERs is necessary for estradiolís anorexigenic effect, that a physiological regimen of estradiol treatment increases the expression of multiple serotonergic genes in the midbrain raphe nuclei, and that estradiol increases the anorexia produced by activation of postsynaptic 5-HT2C receptors. The results of the present studies suggest that estradiol interacts with the 5-HT system to control food intake in the female rat.