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

项目摘要/摘要 甲基苯丙胺(Meth)和酒精(Etoh)被广泛联合滥用，但人们对它们之间的相互作用知之甚少 造成潜在的伤害。尽管这两种药物对外周器官有相似的效果，但这些 在评估他们的个体神经生物学时，炎症等外周效应通常被忽略 效果。此外，Meth和Etoh也有共同的神经化学基础，如增加 谷氨酸神经传递和神经炎症之间的串扰可以预测相加或超过- 当药物同时滥用时，会产生附加的神经效应。因此，可能会导致同时接触甲基溴和乙醇。 神经毒性、兴奋性毒性和神经炎性症状加重。然而，没有研究表明 系统地研究了Meth和Etoh的共同暴露，它们的外围效应，以及 它们的综合外周效应导致神经毒性增强。因此，该提案的目标是 确定涉及特定脑细胞类型的汇聚的外周和中枢神经生物学机制 Meth和Etoh联合暴露的潜在协同神经毒性效应是潜在的。 中心假说是Meth对多巴胺、5-羟色胺终末和神经元的神经毒性作用 被自愿摄入乙醇对肠道的外周促炎作用增强和先于 加重神经炎症和兴奋性谷氨酸神经传递。具体目标1将决定 肠道炎症与自愿饮用乙醇有关，并将先于并加剧 甲硫氨酸的神经毒性作用。特定目标2将定义脑细胞表型及其转录组的变化 与饮用乙醇和酒精影响的炎症介质和谷氨酸传递有关 后来接触到了甲基苯丙胺。具体目标2的成果将指导具体目标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 通过评估谷氨酸神经传递和MEH的兴奋毒性如何影响METH和ETOH 由肠道的外周炎症引起。此外，来自星形胶质细胞的转录变化， 在AIM 2中发现的对外周炎症反应的小胶质细胞和神经元将被检查其 谷氨酸对神经传递的影响。长期目标是突出外围因素的重要性 在调节药物滥用对神经生物学和行为的影响方面制定了一种可行的 针对外周炎症并减轻有害生物的神经保护策略 与共同滥用Meth和Etoh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.