Effect of the estral cycle on central 5-HT levels in intact female rats and that of estrogen replacement treatment in ovariectomized rats

Juan Vásquez-Vásquez, Brenda García-Iglesias, Martha Noyola-Díaz, Esther Martínez-García, Carolina Sánchez-Maldonado, José Terrón
Cinvestav-IPN, Mexico City, Mexico

Extensive clinical evidence suggests a close link between ovarian hormone fluctuations during the menstrual cycle, the serotonin (5-HT) system and migraine. The aim of this work was to analyze the central levels of serotonin (5-HT), as compared with those of noradrenaline (NA) and dopamine (DA), during the estral cycle of intact female rats, and in ovariectomized rats submitted to chronic (14 days) estrogen replacement treatment. The neurotransmitters were quantified by HPLC in the dorsal raphe (DRN) and paraventricular nuclei (PVN) dissected from 300 μm-thick brain slices. Two consecutive 4 day long estral cycles were determined in intact female rats; animals with longer lasting cycles were excluded. Ovariectomized rats were subcutaneously implanted with silastic capsules containing vehicle (cholesterol) and 17β-estradiol for 14 days. A significant increase in the levels of 5-HT, NA and DA was found in the DRN and the PVN during the proestrus, as compared to the other phases of the estral cycle. In ovariectomized rats, chronic estrogen replacement treatment failed to induce any significant change in the content of NA and DA in the DRN and the PVN, but it evoked a significant increase in the content of 5-HT in both nuclei; acute estrogen withdrawal (i.e. 2 days after removing the capsules) induced a significant decrease in 5-HT levels to pretreatment values. These data support the hypothesis: 1) that estrogens play an important role in the modulation of central 5-HT levels; 2) that migraine attacks might be related to a sudden decrease of 5-HT levels in the brain following an estrogen-induced maximum; and 3) that fluctuations of ovarian hormones may be crucial for migraine to occur. The relevance of estrogen-induced changes in the central levels of NA and DA remains to be determined.