Inhibition of synaptosomal high-affinity uptake of dopamine and serotonin by estrogen agonists and antagonists

Abstract High-affinity uptake of dopamine and serotonin into a synaptosomal preparation from rat cerebral cortex was inhibited by a number of estrogen agonists and antagonists in vitro in a stereoselective and competitive manner. The most potent estrogenic inhibitors in the dopaminergic and serotonergic system were ethinylestradiol ( K 1 = 558 nM) and 2-hydroxyethinylestradiol ( K 1 = 226 nM), respectively. Structure-activity relationships are discussed and compared with the effects of estrogens on noradrenaline uptake. However, as all physiologically occurring estrogens inhibited amine uptake only in the micromolar concentration range it seems unlikely that this direct interaction of estrogens with the amine carrier is responsible for the changes in dopamine and serotonin uptake observed during the estrous cycle or after in vivo administration of estrogens and/or progesterone.