Methamphetamine-Alcohol Interactions and Mechanisms of Augmented Toxicity to Brain and Peripheral Organs

甲基苯丙胺-酒精相互作用以及对大脑和周围器官毒性增强的机制

基本信息

批准号：
9381361
负责人：
Bryan K Yamamoto
金额：
$ 50.68万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9381361
关键词：
AMPA Receptors Acute Addictive Behavior Affect Alcohol abuse Alcohol consumption Alcohols Amphetamine Addiction Anti-Inflammatory Agents Anti-inflammatory Appearance Astrocytes Attenuated Behavioral Biological Blood Brain Brain Injuries Calcium Cell surface Clinical Comorbidity Corpus striatum structure Diagnosis Disease Dopamine Drug toxicity Epidemiology Exposure to Genetic Transcription Glutamates Goals ITGAM gene Individual Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory disease of the intestine Intake Interleukin-1 beta Lasers Lead Long-Term Effects Measures Mediating Mediator of activation protein Methamphetamine Microglia Microscopy Mission National Institute of Drug Abuse Nerve Degeneration Nervous System Trauma Neurobiology Neurologic Effect Neurons Organ Outcome Peripheral Pharmaceutical Preparations Phenotype Predisposing Factor Proteins Proteolysis Public Health Rattus Serotonin Serum Slice Suggestion Sum TLR4 gene TNF gene Testing Tight Junctions Tissues Toxic effect Transcript Up-Regulation alcohol use disorder amphetamine use base brain cell cell type cytokine drug of abuse excitotoxicity frontal lobe gut microbiome methamphetamine abuse methamphetamine effect methamphetamine exposure methamphetamine use microbiota monoamine monocyte neurobiological mechanism neurochemistry neuroinflammation neuromechanism neurotoxic neurotoxicity neurotransmission next generation occludin response synergism transcriptome transcriptome sequencing transmission process

项目摘要

Project Summary/Abstract Methamphetamine (Meth) and alcohol (EtOH) are widely co-abused but little is known about how they interact to cause potential harm. Despite the fact that both drugs have similar effects on peripheral organs, these peripheral effects such as inflammation are typically ignored when evaluating their individual neurobiological effects. Moreover, Meth and EtOH also share common neurochemical underpinnings such as increased crosstalk between glutamate neurotransmission and neuroinflammation that would predict additive or supra- additive neurological effects when the drugs are co-abused. Thus, co-exposure to Meth and EtOH may result in an exacerbated neurotoxic, excitotoxic, and neuroinflammatory profile. No studies however, have systematically examined the co-exposure of Meth and EtOH, their peripheral effects, and the contribution of their combined peripheral effects to an enhanced neurotoxicity. Therefore, the objective of the proposal is to identify convergent peripheral and central neurobiological mechanisms involving defined brain cell types that underlie the potential synergistic neurotoxic effects of the co-exposure to Meth and EtOH. The central hypothesis is that the neurotoxic effects of Meth on dopamine and 5HT terminals and neurons are augmented and preceded by the peripheral pro-inflammatory effects of voluntary EtOH intake on the gut to exacerbate neuroinflammation and excitotoxic glutamate neurotransmission. Specific Aim 1 will determine that inflammation in the gut is associated with voluntary EtOH drinking and will precede and exacerbate the neurotoxic effects of Meth. Specific Aim 2 will define the brain cell phenotype and changes in its transcriptome related to inflammatory mediators and glutamate transmission that are affected by EtOH drinking and subsequent exposure to Meth. The outcomes of Specific Aim 2 will guide and be integrated with Specific Aim 3 that will identify the neural mechanisms, consequences, and neurobiological significance of the co-abuse of Meth and EtOH by assessing how glutamate neurotransmission and the excitotoxicity of Meth are influenced by peripheral inflammation from gut. Moreover, transcription changes derived individually from astrocytes, microglia and neurons identified in Aim 2 in response to peripheral inflammation will be examined for their effects of glutamate neurotransmission. The long-term goal is to highlight the importance of peripheral factors in mediating the neurobiological and behavioral effects of drugs of abuse and to develop a feasible neuroprotective strategy that targets peripheral inflammation and mitigates the harmful biological consequences associated with the co-abuse of Meth and EtOH.

项目摘要/摘要甲基苯丙胺（甲基苯丙胺）和酒精（ETOH）被广泛虐待，但对它们如何相互作用知之甚少造成潜在的伤害。尽管两种药物对外围器官都有相似的影响，但这些评估其个体神经生物学时，通常会忽略诸如炎症之类的外围效应效果。此外，甲基苯丙胺和EtOH还共享常见的神经化学基础，例如增加谷氨酸神经传递与神经炎症之间的串扰，可以预测添加剂或上炎当药物共施加时，添加剂神经系统作用。因此，可能会导致甲基甲基甲基苯丙胺的暴露在恶化的神经毒性，兴奋性和神经炎性症状中。但是没有研究，系统地检查了甲基和ETOH的共曝光，它们的外围效应以及的贡献它们的外围效应增强了神经毒性。因此，该提议的目的是确定涉及定义的脑细胞类型的收敛外周和中央神经生物学机制基的基础是共同暴露于Meth和EtOH的潜在协同神经毒性作用。中心假设是甲基对多巴胺和5HT末端和神经元的神经毒性作用增强并在肠道对肠道上的自愿ETOH摄入量的周围促炎作用加剧神经炎症和兴奋性谷氨酸神经传递。具体目标1将确定肠道中的炎症与自愿性EtoH饮酒有关，并将其之前和加剧甲基苯丙胺的神经毒性作用。特定的目标2将定义脑细胞表型及其转录组的变化与受EtoH饮酒和随后暴露于甲基苯丙胺。特定目标2的结果将指导并与特定目标集成 3可以确定神经机制，后果和神经生物学意义通过评估甲基酸酯神经传递和甲基毒性的兴奋性如何受到甲基甲酸酯神经传递的影响，甲基和ETOH受到影响通过肠道外周炎症。此外，从星形胶质细胞中分别得出的转录变化，在AIM 2中鉴定出对周围炎症的小胶质细胞和神经元将检查其谷氨酸神经传递的影响。长期目标是强调外围因素的重要性介导滥用药物的神经生物学和行为影响，并发展可行靶向周围炎症并减轻有害生物学的神经保护策略与甲基苯丙胺和eTOH的共施用相关的后果。