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

项目概要/摘要 甲基苯丙胺（Methe）和酒精（EtOH）被广泛滥用，但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有相似的作用， 当评价其个体神经生物学特性时， 方面的影响.此外，甲基和乙醇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，可以预测附加或超- 当药物被共同滥用时，会产生叠加的神经效应。因此，共同暴露于甲基和乙醇可能导致 神经毒性、兴奋性毒性和神经炎性特征加剧。然而，没有研究表明， 系统地检查了甲基和乙醇的共同暴露，其外周效应，以及 它们的外周效应结合起来会增强神经毒性。因此，该提案的目的是 确定涉及确定的脑细胞类型的会聚外周和中枢神经生物学机制， 共同暴露于甲基和乙醇的潜在协同神经毒性作用的基础。 中心假设是，Meth对多巴胺和5-HT终末和神经元的神经毒性作用 增强和之前的外周促炎作用的自愿EtOH摄入对肠道， 加剧神经炎症和兴奋毒性谷氨酸神经传递。具体目标1将确定， 肠道中的炎症与自愿的EtOH饮用相关，并且将先于并加剧 Meth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 与炎症介质和谷氨酸传输相关，受乙醇饮用影响， 随后暴露于甲基苯丙胺。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，将确定的神经机制，后果，和神经生物学意义的共同滥用的 通过评估如何影响谷氨酸神经传递和甲基的兴奋性毒性 由肠道周围炎症引起此外，转录变化分别来自星形胶质细胞， 将检查目标2中识别的响应于外周炎症的小胶质细胞和神经元的 谷氨酸神经传递的影响。长期目标是突出外围因素的重要性 在调解滥用药物的神经生物学和行为影响，并制定一个可行的 神经保护策略，靶向外周炎症并减轻有害的生物学反应。 与甲基和乙醇共同滥用相关的后果。

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.