Department of Neuroscience, West Virginia University, Morgantown, USA.
Department of Behavioral Medicine and Psychiatry, West Virginia University, Morgantown, USA.
J Psychopharmacol. 2020 Dec;34(12):1393-1407. doi: 10.1177/0269881120944160. Epub 2020 Aug 25.
Regulator of G protein Signaling (RGS) proteins inhibit G protein-coupled receptor (GPCR) signaling, including the signals that arise from neurotransmitter release. We have shown that RGS12 loss diminishes locomotor responses of C57BL/6J mice to dopamine transporter (DAT)-targeting psychostimulants. This diminution resulted from a brain region-specific upregulation of DAT expression and function in RGS12-null mice. This effect on DAT prompted us to investigate whether the serotonin transporter (SERT) exhibits similar alterations upon RGS12 loss in C57BL/6J mice.
Does RGS12 loss affect (a) hyperlocomotion to the preferentially SERT-targeting psychostimulant 3,4-methylenedioxymethamphetamine (MDMA), (b) SERT expression and function in relevant brain regions, and/or (c) serotonergically modulated behaviors?
Open-field and spontaneous home-cage locomotor activities were quantified. 5-HT, 5-HIAA, and SERT levels in brain-region homogenates, as well as SERT expression and function in brain-region tissue preparations, were measured using appropriate biochemical assays. Serotonergically modulated behaviors were assessed using forced swim and tail suspension paradigms, elevated plus and elevated zero maze tests, and social interaction assays.
RGS12-null mice displayed no hyperlocomotion to 10 mg/kg MDMA. There were brain region-specific alterations in SERT expression and function associated with RGS12 loss. Drug-naïve RGS12-null mice displayed increases in both anxiety-like and anti-depressive-like behaviors.
RGS12 is a critical modulator of serotonergic neurotransmission and serotonergically modulated behavior in mice; lack of hyperlocomotion to low dose MDMA in RGS12-null mice is related to an alteration of steady-state SERT expression and 5-HT uptake.
G 蛋白信号调节蛋白（RGS）抑制 G 蛋白偶联受体（GPCR）信号转导，包括神经递质释放引起的信号。我们已经表明，RGS12 缺失会减弱 C57BL/6J 小鼠对多巴胺转运蛋白（DAT）靶向精神兴奋剂的运动反应。这种减少是由于 RGS12 缺失的小鼠中特定脑区 DAT 表达和功能的上调。这种对 DAT 的影响促使我们研究 RGS12 缺失是否会导致 5-羟色胺转运体（SERT）在 C57BL/6J 小鼠中发生类似的改变。
RGS12 缺失是否会影响（a）对优先靶向 SERT 的精神兴奋剂 3,4-亚甲二氧基甲基苯丙胺（MDMA）的过度运动，（b）相关脑区的 SERT 表达和功能，和/或（c）5-羟色胺能调节的行为？
量化了旷场和自发笼内运动活动。使用适当的生化测定法测量了脑区匀浆中的 5-HT、5-HIAA 和 SERT 水平，以及脑区组织制剂中的 SERT 表达和功能。使用强迫游泳和尾部悬挂范式、高架十字迷宫和高架零迷宫测试以及社交互动测试评估了 5-羟色胺能调节的行为。
RGS12 缺失的小鼠对 10mg/kg MDMA 没有过度运动。RGS12 缺失与 SERT 表达和功能的脑区特异性改变有关。未用药的 RGS12 缺失的小鼠表现出焦虑样和抗抑郁样行为的增加。
RGS12 是小鼠中 5-羟色胺能神经传递和 5-羟色胺能调节行为的关键调节剂；RGS12 缺失的小鼠对低剂量 MDMA 没有过度运动，这与 SERT 表达和 5-HT 摄取的稳态改变有关。
