Natural and Synthetic Corticosteroids Inhibit Uptake₂-Mediated Transport in CNS Neurons

Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Abstract: In addition to exerting actions via mineralocorticoid and glucocorticoid receptors, corticosteroids also act by inhibiting uptake2, a high-capacity monoamine transport system originally described in peripheral tissues. Recent studies have demonstrated that uptake2 transporters are expressed in the brain and play roles in monoamine clearance, suggesting that they mediate some corticosteroid effects on physiological and behavioral processes. However, the sensitivity of brain uptake2 to many natural and synthetic corticosteroids has not been characterized. Cultured rat cerebellar granule neurons (CGNs) were previously shown to exhibit corticosterone-sensitive accumulation of the uptake2 substrate1-methyl-4-phenylpyridinium (MPP +). We examined the expression of uptake1 and uptake2 transporters in CGNs, and tested the effects of a variety of natural and synthetic corticosteroids on accumulation of [ 3 H]-MPP + by these cells. Cultured rat CGNs expressed mRNA for three uptake2-like transporters: organic cation transporters 1 and 3, and the plasma membrane monoamine transporter. They did not express mRNA for the dopamine or norepinephrine transporters, and expressed very little mRNA for the serotonin reuptake transporter. Accumulation of [ 3 H]-MPP + by CGNs was dose-dependently inhibited by corticosterone and decynium-22, known inhibitors of uptake2. Accumulation of MPP + was also dose-dependently inhibited, with varying efficacies, by aldosterone, 11-deoxycorticosterone, cortisol, and cortisone, and by the synthetic glucocorticoids betamethasone, dexamethasone and prednisolone, and the glucocorticoid receptor antagonist RU38486. These studies demonstrate that uptake2 in the CNS is inhibited by a variety of natural and synthetic corticosteroids, and suggest that inhibition of uptake2-mediated monoamine clearance may underlie some behavioral and physiological effects of these hormones.