Estrogen-dependent effects of 5-hydroxytryptophan on cortical spreading depression in rat: Modelling the serotonin-ovarian hormone interaction in migraine aura

Abstract

Background Cortical spreading depression (CSD) is the likely culprit of the migraine aura. Migraine is sexually dimorphic and thought to be a “low 5-HT” condition. We sought to decipher the interrelation between serotonin, ovarian hormones and cortical excitability in a model of migraine aura. Methods Occipital KCl-induced CSDs were recorded for one hour at parieto-occipital and frontal levels in adult male (n = 16) and female rats (n = 64) one hour after intraperitoneal (i.p.) injection of 5-hydroxytryptophan (5-HTP) or NaCl. Sixty-five oophorectomized females were treated with estradiol- (E2) or cholesterol- (Chol) filled capsules. Two weeks later we recorded CSDs after 5-HTP/NaCl injections before or 20 hours after capsule removal. Results 5-HTP had no effect in males, but decreased CSD frequency in cycling females, significantly so during estrus, at parieto-occipital (−3.5CSD/h, p < 0.001) and frontal levels (−2.5CSD/h, p = 0.014). In oophorectomized rats, CSD susceptibility increased during E2 treatment at both recording sites (+5CSD/h, p = 0.001 and +3CSD/h, p < 0.01), but decreased promptly after E2 withdrawal (−4.7CSD/h, p < 0.001 and −1.7CSD/h, p = 0.094). The CSD inhibitory effect of 5-HTP was significant only in E2-treated rats (−3.4CSD/h, p = 0.006 and −1.8CSD/h, p = 0.029). Neither the estrous cycle phase, nor E2 or 5-HTP treatments significantly modified CSD propagation velocity. Conclusion 5-HTP decreases CSD occurrence in the presence of ovarian hormones, suggesting its potential efficacy in migraine with aura prophylaxis in females. Elevated E2 levels increase CSD susceptibility, while estrogen withdrawal decreases CSD. In a translational perspective, these findings may explain why migraine auras can appear during pregnancy and why menstrual-related migraine attacks are rarely associated with an aura.