Gasser Paul J, Lowry Christopher A, Orchinik Miles
School of Life Sciences, Arizona State University, Tempe, Arizona 85287-4501, USA.
J Neurosci. 2006 Aug 23;26(34):8758-66. doi: 10.1523/JNEUROSCI.0570-06.2006.
Glucocorticoid hormones act within the brain to alter physiological and behavioral responses to stress-related stimuli. Previous studies indicated that acute stressors can increase serotonin [5-hydroxytryptamine (5-HT)] concentrations in the dorsomedial hypothalamus (DMH), a midline hypothalamic structure involved in the integration of physiological and behavioral responses to stress. The current study tests the hypothesis that rapid, stress-induced accumulation of 5-HT is attributable to the inhibition of 5-HT transport via organic cation transporters (OCTs). OCTs are a family of high-capacity, bidirectional, multispecific transporters of organic cations (including 5-HT, dopamine, and norepinephrine) only recently described in brain. In peripheral tissues, organic cation transport via some OCTs is inhibited by corticosterone. We examined the expression and function of OCTs in the periventricular medial hypothalamus of male Sprague Dawley rats using reverse-transcriptase (RT)-PCR, immunohistochemistry, and in vitro transport assays. RT-PCR revealed expression of OCT3 mRNA, but not OCT1 or OCT2 mRNA, in the medial hypothalamus. OCT3-like immunoreactivity was observed in ependymal and glial-like cells in the DMH. Acutely prepared minces of rat medial hypothalamic tissue accumulated the OCT substrates [3H]-histamine and [3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+). Consistent with the pharmacological profile of OCT3, corticosterone, 5-HT, estradiol, and the OCT inhibitor decynium22 dose-dependently inhibited histamine accumulation. Corticosterone and decynium22 also inhibited efflux of [3H]-MPP+ from hypothalamic minces. These data support the hypothesis that corticosterone-induced inhibition of OCT3 mediates stress-induced accumulation of 5-HT in the DMH and suggest that corticosterone may acutely modulate physiological and behavioral responses to stressors by altering serotonergic neurotransmission in this brain region.
糖皮质激素在脑内发挥作用，改变机体对应激相关刺激的生理和行为反应。以往研究表明，急性应激源可增加背内侧下丘脑（DMH）中的血清素[5-羟色胺（5-HT）]浓度，DMH是下丘脑的一个中线结构，参与机体对应激的生理和行为反应的整合。本研究检验了以下假说：应激诱导的5-HT快速积累归因于有机阳离子转运体（OCTs）对5-HT转运的抑制作用。OCTs是一类高容量、双向、多特异性的有机阳离子转运体（包括5-HT、多巴胺和去甲肾上腺素），最近才在脑内被描述。在周围组织中，皮质酮可抑制某些OCTs介导的有机阳离子转运。我们使用逆转录酶（RT）-PCR、免疫组织化学和体外转运试验，研究了雄性Sprague Dawley大鼠室周内侧下丘脑OCTs的表达和功能。RT-PCR显示，内侧下丘脑表达OCT3 mRNA，但不表达OCT1或OCT2 mRNA。在DMH的室管膜细胞和胶质样细胞中观察到OCT3样免疫反应性。急性制备的大鼠内侧下丘脑组织匀浆可积累OCT底物[3H]-组胺和[3H]-N-甲基-4-苯基吡啶鎓（[3H]-MPP+）。与OCT3的药理学特性一致，皮质酮、5-HT、雌二醇和OCT抑制剂癸甲氯铵22可剂量依赖性地抑制组胺积累。皮质酮和癸甲氯铵22也抑制[3H]-MPP+从下丘脑匀浆中的流出。这些数据支持以下假说：皮质酮诱导的OCT3抑制介导了应激诱导的DMH中5-HT的积累，并提示皮质酮可能通过改变该脑区的5-羟色胺能神经传递，急性调节机体对应激源的生理和行为反应。
