Vagus nerve stimulation increases basal dopamine levels in the brain to decrease methamphetamine-mediated responses

摘要 这项研究的长期目标是确定迷走神经刺激(Vns)如何调节基础多巴胺。 多巴胺神经元的传递和甲基苯丙胺调节。滥用甲基苯丙胺是一种主要的公共行为 世界各地的健康问题，但还没有有效的药物疗法来治疗甲基苯丙胺 上瘾。甲基苯丙胺是一种有效的精神刺激剂，通过靶向增加细胞外多巴胺水平 中脑和纹状体的多巴胺转运体(DAT)。在这笔赠款的前一个周期中，我们证明了 甲基苯丙胺与DAT介导的多巴胺摄取竞争，通过DAT增加多巴胺的外流， 增加DAT介导的内向去极化电流，导致多巴胺神经元放电活动增强。 甲基苯丙胺增加多巴胺神经元中的钙离子水平，从而增强对动作电位的依赖 和独立的多巴胺释放(即多巴胺外流)。我们还发现，神经元去极化诱导 DAT内化导致多巴胺和甲基苯丙胺摄取减少。多项研究表明 VNS增加了中脑区的多巴胺水平，并减少了可卡因寻找行为，尽管 迷走神经和中脑区之间的多突触连接机制不明。我们发现 光遗传刺激支配上胃肠道的迷走神经感觉神经元去极化 并增加中脑多巴胺神经元的基础放电活动，持续至少30分钟。 组织学分析显示c-fos阳性神经元的体树突状DAT减少。这些数据是 与我们之前的报告一致的是，神经元去极化诱导DAT内化，这可以减少 甲基苯丙胺对多巴胺传递的调节作用。我们的初步数据还显示， 光遗传VNS增加了没有达到上限水平的细胞外多巴胺水平，但它降低了 甲基苯丙胺刺激多巴胺神经元，通过去极化多巴胺神经元，降低DAT水平。 这些初步数据和文献支持最重要的假设，即VNS增加基础多巴胺 通过去极化多巴胺神经元，降低DAT水平，并减少甲基苯丙胺对 多巴胺的传递从而减弱了甲基苯丙胺的行为和细胞反应。我们的建议 研究将确定VNS的潜在细胞机制-调节多巴胺传递和 甲基苯丙胺引起的反应。

Abstract The long-term goal of this study is to determine how vagus nerve stimulation (VNS) regulates basal dopamine transmission and methamphetamine regulation of dopamine neurons. Methamphetamine abuse is a major public health issue around the world, yet there are no effective pharmacotherapies for the treatment of methamphetamine addiction. Methamphetamine is a potent psychostimulant that increases extracellular dopamine levels by targeting the dopamine transporter (DAT) in the midbrain and striatum. In the previous cycle of this grant, we shown that methamphetamine competes with the DAT-mediated dopamine uptake, increases dopamine efflux via the DAT, increases the DAT mediated inward depolarizing current leading to increased firing activity of dopamine neurons. Methamphetamine increases Ca2+ levels in the dopamine neurons that enhances both action potential dependent and independent dopamine release (i.e., dopamine efflux). We also found that neuronal depolarization induces DAT internalization leading to decreased dopamine and methamphetamine uptake. Multiple studies have shown that VNS increases dopamine levels in the midbrain region and reduces cocaine seeking behavior, albeit with an unknown mechanism via a multi-synaptic connection between vagus nerve and midbrain region. We found that optogenetic stimulation of vagal sensory neurons innervating the upper gastrointestinal tract depolarizes dopamine neurons and increases basal firing activity of midbrain dopamine neurons lasting for at least 30 minutes. Histological analyses revealed a reduction in somatodendritic DAT in the c-fos positive neurons. These data are consistent with our previous report showing neuronal depolarization induces DAT internalization, that can reduce the efficacy of methamphetamine regulation of dopamine transmission. Our preliminary data also revealed that optogenetic VNS increases extracellular dopamine levels that does not reach ceiling levels, but it reduces the methamphetamine stimulation of dopamine neurons, by depolarizing dopamine neurons, reducing DAT levels. These preliminary data and the literature support the overarching hypothesis that VNS increases basal dopamine levels by depolarizing dopamine neurons, reducing DAT levels, and decreasing methamphetamine-stimulation of dopamine transmission thereby attenuating methamphetamine’s behavioral and cellular responses. Our proposed studies will determine the underlying cellular mechanism for VNS-regulation of dopamine transmission and methamphetamine-induced responses.