Natural and synthetic corticosteroids inhibit uptake2-mediated transport in CNS neurons

Abstract

In addition to exerting actions via mineralocorticoid and glucocorticoid receptors, corticosteroids also act by inhibiting uptake2, a highcapacity 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 corticosteronesensitive 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.

Glucocorticoid receptors in the prefrontal cortex regulate stress-evoked dopamine efflux and aspects of executive function

“…However, neither the enzymatic activity nor gene expression levels of catechol-O-methyltransferase or monoamine oxidase in the mPFC change after treatment with corticosterone (33). More recent evidence suggests that corticosterone can inhibit a high-capacity monoamine uptake transport system, which plays a key role in monoamine clearance (34). Future studies to examine the intracellular mechanisms governing the release of DA by GRs in the mPFC are warranted.…”

Production and Function of Serotonin in Cardiac Cells

“…Classically, re-uptake of 5-HT (but also of neurotransmitters like histamine, noradrenaline, or dopamine) into nerve cells has been called uptake 1 and is assumed to be mediated for 5-HT by SERT (and by dopamine transporter (DAT) for dopamine, as well as by noradrenaline transporter (NAT = NET) for noradrenaline, however, their specificity of transport shows some overlap, which may explain compensations in knockout mouse models [63]). SERT is blocked by some antidepressant drugs like fluoxetine.…”

“…Another difference between uptake 1 and 2 relies on the fact that uptake 2 is much less specific for 5-HT than uptake 1. Usually, proteins that comprise uptake 2 will also transport other neurotransmitters like dopamine and noradrenaline [63]. Uptake 2 is usually inhibited by cortisone (but also by synthetic dexamethasone, by aldosterone, and by budesonide) via unknown mechanisms and divergent specificity for OCT1-3 and PMAT [63,74]) and more specifically by decynium 22 [57,63].…”

“…Usually, proteins that comprise uptake 2 will also transport other neurotransmitters like dopamine and noradrenaline [63]. Uptake 2 is usually inhibited by cortisone (but also by synthetic dexamethasone, by aldosterone, and by budesonide) via unknown mechanisms and divergent specificity for OCT1-3 and PMAT [63,74]) and more specifically by decynium 22 [57,63]. At higher concentrations of 5-HT (10 μM), it is mainly transported via uptake 2 (in synaptosomes, regarding decynium 22 as uptake 2-specific [57]).…”

“…At higher concentrations of 5-HT (10 μM), it is mainly transported via uptake 2 (in synaptosomes, regarding decynium 22 as uptake 2-specific [57]). In the CNS, proteins responsible for uptake 2 have been detected not only in nerve cells but also in non-nerve cells (glial cells [63]). Uptake 2 is functionally relevant in the heart because decynium 22 affects the concentration response curve of 5-HT on force of contraction in isolated atrium of 5-HT 4 -receptor overexpressing mice [24].…”