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

迷走神经刺激会增加大脑中的基础多巴胺水平，从而减少甲基苯丙胺介导的反应

• 批准号: 10648045
• 负责人: Habibeh Khoshbouei
• 金额: $ 54.17万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648045
• 关键词: Action Potentials; Acute; Affect; Afferent Neurons; Attenuated; Behavior; Behavioral; Biochemical; Biological Assay; Biotinylation; Brain; Cells; Corpus striatum structure; Data; Dopamine; Exhibits; FOS gene; Future; Goals; Grant; Halorhodopsins; Histologic; Image; Immunohistochemistry; Injections; Light; Literature; LoxP-flanked allele; Measurement; Mediating; Membrane; Methamphetamine; Methamphetamine dependence; Microinjections; Midbrain structure; Molecular Conformation; Mus; N-Methylaspartate; NR1 gene; Neurons; Nodose Ganglion; Optics; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylation; Preparation; Property; Public Health; Regulation; Reporting; Rewards; Slice; Synapses; Testing; Translating; Upper digestive tract structure; Vagus nerve structure; Viral; behavioral response; biophysical analysis; cocaine seeking; combinatorial; conditioned place preference; desensitization; dopamine transporter; dopaminergic neuron; extracellular; in vivo; methamphetamine abuse; methamphetamine exposure; mouse model; neurophysiology; neurotransmitter release; optogenetics; prevent; psychostimulant; response; transcriptomics; transmission process; uptake; vagus nerve stimulation

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.

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 传递和甲基苯丙胺调节多巴胺神经元。甲基苯丙胺滥用是一个主要的公众 世界各地的健康问题，但没有有效的药物治疗甲基苯丙胺 成瘾甲基苯丙胺是一种有效的精神兴奋剂，通过靶向增加细胞外多巴胺水平， 中脑和纹状体中的多巴胺转运体（DAT）。在上一个赠款周期中，我们表明， 甲基苯丙胺与DAT介导的多巴胺摄取竞争，增加通过DAT的多巴胺流出， 增加DAT介导的内向去极化电流，导致多巴胺神经元的放电活性增加。 甲基苯丙胺增加多巴胺神经元中的Ca 2+水平，这增强了动作电位依赖性 和独立的多巴胺释放（即，多巴胺流出）。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增加了中脑区域的多巴胺水平，减少了可卡因寻求行为，尽管 迷走神经和中脑区域之间的多突触连接的未知机制。我们发现 支配上胃肠道的迷走神经感觉神经元的光遗传学刺激去极化 多巴胺神经元，并增加持续至少30分钟的中脑多巴胺神经元的基础放电活动。 组织学分析显示c-fos阳性神经元的体树突DAT减少。这些数据 与我们以前的报告一致，显示神经元去极化诱导DAT内化，这可以减少 甲基苯丙胺调节多巴胺传递的功效。我们的初步数据还显示， 光遗传学VNS增加细胞外多巴胺水平，但没有达到上限水平，但它降低了细胞外多巴胺水平。 甲基苯丙胺刺激多巴胺神经元，通过使多巴胺神经元去极化，降低DAT水平。 这些初步数据和文献支持VNS增加基础多巴胺的总体假设 通过去极化多巴胺神经元，降低DAT水平，减少甲基苯丙胺刺激， 多巴胺传递，从而减弱甲基苯丙胺的行为和细胞反应。我们提出的 研究将确定VNS调节多巴胺传递的潜在细胞机制， 甲基苯丙胺引起的反应