METHAMPHETAMINE AND GDNF/BDNF IN AGED DOPAMINE SYSTEMS

老年多巴胺系统中的甲基苯丙胺和 GDNF/BDNF

• 批准号: 6957281
• 负责人: Jacqueline F. McGinty
• 金额: $ 12.5万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6957281
• 关键词: aging; antibacterial agents; antiinflammatory agents; behavior test; brain derived neurotrophic factor; dopamine; drug interactions; gene environment interaction; gene expression; gene mutation; genetic susceptibility; immunocytochemistry; in situ hybridization; laboratory mouse; longitudinal animal study; methamphetamine; microarray technology; neural transmission; neuropharmacology; neurotoxicology; neurotrophic factors; pharmacogenetics; psychomotor function; tetracyclines; western blottings

The proposed experiments in Project 0002 will assess the impact of challenges to DA systems on the natural decline of these systems that accompany the aging process. Reductions in glial cell derived neurotrophic factor (GDNF+/-) or brain-derived neurotrophic factor (BDNF+/-) via gene deletion and methamphetamine (METH) exposure all produce long-term alterations in DA neural system structure and/or function. The general working hypothesis for the proposed experiments is that the interaction of repeated METH with either GDNF or BDNF reduction will exacerbate the structural and functional changes of DA systems that accompany the aging process. To test this hypothesis, male and female GDNF+/- or BDNF+/- mice exposed to METH as young adults will be examined at 3, 12, 18, and 24 months of age. Effects of these treatment combinations on DA systems will be examined using two strategies: (1) Immunocytochemical staining procedures will be used to assess the integrity of DA and medium spiny striatal neurons and whether the anti-inflammatory drug, minocycline, will block METH toxicity, (2) gene expression experiments (Affymetrix GeneChips and in situ hybridization) followed by the assessment of relevant proteins by immunoblotting will be used to identify changes in the functional properties of the DA neurons. The results of these experiments will integrate with the microglia experiments described in Project 0003 and the DAT and VMAT2 evaluations of Project 0004 to provide information about how some likely genetic and environmental factors might contribute to the different rates of declining DA function noted in the aging population. The significance of these studies is that they will determine whether a mutation in a genetic susceptibility factor (either GDNF or BDNF) combined with a commonly encountered environmental insult (METH) exacerbates the age-related decline of the dopamine systems. This investigation has the potential to identify associated genes and proteins that can be manipulated and re-introduced into the model in the future in order to attenuate the impact of multiple insults on the decline of dopamine neuronal function during aging.

项目0002中提出的实验将评估挑战对DA系统对伴随老化过程的自然衰落的影响。通过基因缺失和甲基苯丙胺（甲基苯丙胺）暴露的降低神经胶质细胞得出的神经营养因子（GDNF +/-）或脑衍生的神经营养因子（BDNF +/-）的降低均在DA神经系统结构和/或功能中产生长期变化。一般的工作假设 提出的实验是，重复的METH与GDNF或BDNF还原的相互作用会加剧伴随衰老过程的DA系统的结构和功能变化。为了检验这一假设，将在3、12、18和24个月大时检查男性和雌性GDNF +/-或BDNF +/-小鼠。这些治疗组合对DA系统的影响将使用两种策略进行检查：（1）免疫细胞化学染色程序将用于评估DA和中刺纹状体神经元的完整性，以及抗炎药，米诺环素，是否会阻止甲基毒性毒性（2）基因表达实验（2）基因介质（2）基因疗法（2）Serectrizations（2）Serectrizations（2）Serectrizations（2）Serectrizations（2）Serectrization（2）免疫印迹将用于识别DA神经元功能特性的变化。这些实验的结果将与项目0003中描述的小胶质细胞实验以及DAT和VMAT2集成 对项目0004的评估，以提供有关某些可能遗传和环境因素可能导致衰老人群中DA功能下降的率不同的信息。这些研究的意义在于，它们将确定遗传敏感性因子（GDNF或BDNF）中的突变是否加上通常遇到的环境损伤（METH）加剧了多巴胺系统与年龄相关的下降。这项研究具有鉴定可以操纵的相关基因和蛋白质的潜力 并将将来重新引入该模型，以减轻多种侮辱对衰老过程中多巴胺神经元功能下降的影响。