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

项目概要/摘要 甲基苯丙胺 (Meth) 和酒精 (EtOH) 被广泛共同滥用，但人们对它们如何相互作用知之甚少 造成潜在的伤害。尽管这两种药物对外周器官具有相似的作用，但这些药物 在评估其个体神经生物学时，通常会忽略炎症等外周影响 影响。此外，冰毒和乙醇也具有共同的神经化学基础，例如增加 谷氨酸神经传递和神经炎症之间的串扰可以预测加性或超性 当药物同时滥用时，会产生附加的神经系统效应。因此，同时接触 Meth 和 EtOH 可能会导致 神经毒性、兴奋性毒性和神经炎症加剧。然而没有研究表明 系统地研究了甲基苯丙胺和乙醇的共同暴露、它们的周边效应以及 它们的联合外周效应增强了神经毒性。因此，该提案的目标是 识别涉及特定脑细胞类型的会聚外周和中枢神经生物学机制 是同时接触甲基苯丙胺和乙醇的潜在协同神经毒性作用的基础。 中心假设是冰毒对多巴胺和 5HT 末端以及神经元的神经毒性作用 自愿摄入 EtOH 对肠道的外周促炎作用会增强并先于这些作用 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 肠道炎症与自愿饮用乙醇有关，并且会先于并加剧 甲基苯丙胺的神经毒性作用。具体目标 2 将定义脑细胞表型及其转录组的变化 与受乙醇饮酒影响的炎症介质和谷氨酸传输有关 随后接触冰毒。具体目标 2 的成果将指导并与具体目标相结合 3 将确定共同滥用的神经机制、后果和神经生物学意义 冰毒和乙醇通过评估谷氨酸神经传递和冰毒的兴奋毒性如何受到影响 由肠道外周炎症引起。此外，星形胶质细胞单独产生的转录变化， 将检查目标 2 中识别的响应外周炎症的小胶质细胞和神经元 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 调节滥用药物的神经生物学和行为影响并制定可行的 针对周围炎症并减轻有害生物的神经保护策略 与同时滥用冰毒和乙醇有关的后果。

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.