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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的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的调节甲基苯丙胺滥用是一个主要的公共问题。甲基苯丙胺是世界各地的健康问题，但目前尚无有效的药物疗法来治疗甲基苯丙胺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。在本次资助的上一个周期中，我们证明了中脑和纹状体中的多巴胺转运蛋白（DAT）。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动增加。甲基苯丙胺可增加多巴胺神经元中的 Ca2+ 水平，从而增强动作电位依赖性和独立的多巴胺释放（即多巴胺流出）我们还发现神经去极化诱导。多项研究表明，DAT 内化会导致多巴胺和甲基苯丙胺的摄取减少。 VNS 会增加中脑区域的多巴胺水平并减少可卡因寻求行为，尽管我们发现通过迷走神经和中脑区域之间的多突触连接的未知机制。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 阳性神经元中体细胞树突 DAT 减少。与我们之前的报告一致，显示神经去极化诱导 DAT 内化，这可以减少我们的初步数据还表明，甲基苯丙胺调节多巴胺传递的功效。光遗传学 VNS 增加了未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通过去极化多巴胺神经元刺激多巴胺神经元，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 水平和减少甲基苯丙胺刺激多巴胺传输从而减弱甲基苯丙胺的行为和细胞反应。研究将确定 VNS 调节多巴胺传输的潜在细胞机制甲基苯丙胺引起的反应。