Marquette University, Department of Biomedical Sciences, Milwaukee, WI 53233, USA.
Physiol Behav. 2011 Aug 3;104(2):306-11. doi: 10.1016/j.physbeh.2010.11.012. Epub 2010 Nov 21.
In addition to exerting actions via mineralocorticoid and glucocorticoid receptors, corticosteroids also act by inhibiting uptake(2), a high-capacity monoamine transport system originally described in peripheral tissues. Recent studies have demonstrated that uptake(2) 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 uptake(2) 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 uptake(2) substrate 1-methyl-4-phenylpyridinium (MPP(+)). We examined the expression of uptake(1) and uptake(2) 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 uptake(2)-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 uptake(2). 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 uptake(2) in the CNS is inhibited by a variety of natural and synthetic corticosteroids, and suggest that inhibition of uptake(2)-mediated monoamine clearance may underlie some behavioral and physiological effects of these hormones.
除了通过盐皮质激素和糖皮质激素受体发挥作用外，皮质类固醇还通过抑制摄取（2）发挥作用，摄取（2）是一种最初在周围组织中描述的高容量单胺转运系统。最近的研究表明，摄取（2）转运体在大脑中表达，并在单胺清除中发挥作用，这表明它们介导了一些皮质类固醇对生理和行为过程的影响。然而，大脑摄取（2）对许多天然和合成皮质类固醇的敏感性尚未得到描述。先前的研究表明，培养的大鼠小脑颗粒神经元（CGNs）表现出皮质酮敏感的摄取（2）底物 1-甲基-4-苯基吡啶（MPP（+））的积累。我们检查了 CGNs 中摄取（1）和摄取（2）转运体的表达，并测试了各种天然和合成皮质类固醇对这些细胞中[（3）H] -MPP（+）积累的影响。培养的大鼠 CGNs 表达了三种摄取（2）样转运体的 mRNA：有机阳离子转运体 1 和 3 以及质膜单胺转运体。它们不表达多巴胺或去甲肾上腺素转运体的 mRNA，并且表达的 5-羟色胺再摄取转运体的 mRNA 很少。CGNs 中[（3）H] -MPP（+）的积累被皮质酮和去甲金雀花碱（已知的摄取（2）抑制剂）剂量依赖性地抑制。MPP（+）的积累也被各种天然和合成皮质类固醇剂量依赖性地抑制，具有不同的功效，包括醛固酮、11-脱氧皮质酮、皮质醇和可的松，以及合成的糖皮质激素倍他米松、地塞米松和泼尼松龙，以及糖皮质激素受体拮抗剂 RU38486。这些研究表明，中枢神经系统中的摄取（2）被各种天然和合成皮质类固醇抑制，并表明抑制摄取（2）介导的单胺清除可能是这些激素产生一些行为和生理效应的基础。
