BDNF, Dopamine and Ethanol

描述(由候选人提供)：我的短期目标是在一所授予博士学位的大学获得一份终身教职。我的长期目标是领导一个神经化学研究小组，专注于长期接触酒精所产生的神经适应。为了了解酒精中毒所产生的神经适应，我的实验室将使用体内微透析和体外伏安法两种生物传感器技术来评估神经递质多巴胺。在美国，大约有2000万人遭受酒精滥用，每年导致约2000亿美元的损失。这项建议有两个目的(1)通过使用脑源性神经营养因子(BDNF)水平下降50%的小鼠来了解脑源性神经营养因子(BDNF)和大脑中多巴胺之间的相互作用；(2)评估长期酒精暴露对对照组和BDNF中多巴胺系统的影响。最终目的是确定脑源性神经营养因子和多巴胺之间的失衡是否会导致酗酒或保护大脑免受与成瘾过程相关的生化适应的表达。大多数滥用药物，如乙醇，都有能力提高大脑区域如尾壳核和伏隔核的细胞外多巴胺水平。这种多巴胺的释放被认为在滥用药物的兴奋剂特性中发挥着重要作用。最近的证据表明，BDNF能够调节多巴胺的神经传递，但最直接的证据表明，BDNF控制着多巴胺D3受体。利用体内微透析技术，将在对照组和BDNF小鼠中评估存在或不存在多巴胺D3受体激动剂时的细胞外多巴胺水平。接下来，体外伏安实验将检测BDNF水平降低对多巴胺释放、摄取和多巴胺D3受体的影响。我们假设BDNF小鼠将具有低BDNF水平和低功能的多巴胺系统，导致倾向于饮酒更多。第二个目标是评估BDNF和对照组小鼠在长期饮酒三天后的多巴胺系统。我们假设慢性酒精会降低内源性BDNF和DA水平。利用体内微渗析和体外伏安法，我们将对乙醇戒断3天后的多巴胺系统进行表征。这项研究的影响是提高我们对酒精滥用分子机制的了解，努力开发更好的治疗方法和/或治疗方法。

DESCRIPTION (provided by candidate): My immediate short-term goal is to obtain a tenure-track faculty position at a Ph.D. granting university. My long-term goal is to lead a neurochemistry research group focusing on the neuroadapations produced by long-term exposure to alcohol. In order to understand the neuroadaptions produced by alcoholism, my laboratory will use two biosensor techniques in vivo microdialysis and in vitro voltammetry to evaluate the neurotransmitter dopamine. Approximately, 20 million people within the United States endure alcohol abuse, which leads to about $200 billion dollars lost per year. This proposal has two aims (1) to understand the interaction between brain derived neurotrophic factor (BDNF) and dopamine in the brain by using mice that have a 50% reduction in BDNF levels (BDNF) and (2) to evaluate the effects of chronic alcohol exposure on the dopamine system in control and BDNF. The ultimate objective is to determine if an imbalance between BDNF and dopamine may lead to abuse of alcohol or protect the brain from expressing biochemical adaptions associated with the addiction process. Most drugs of abuse; like ethanol, have the ability to elevate extracellular dopamine levels in brain areas such as the caudate-putamen and nucleus accumbens. This dopamine release is thought to play an important role in the stimulant properties of drugs of abuse. Recent evidence shows that BDNF is able to modulate dopamine neurotransmission, but the most direct evidence illustrates BDNF's control over the dopamine D3 receptor. Using in vivo microdialysis, extracellular dopamine levels will be evaluated in the presence or absence of dopamine D3 receptor agonist in control and BDNF mice. Next, in vitro voltammetry experiments will examine the effect of reduced levels of BDNF on dopamine release, uptake and the dopamine D3 receptor. We hypothesize BDNF mice will have low BDNF levels and a low functioning dopamine system, resulting in a tendency to drink greater amounts of alcohol. The second goal is to evaluate the dopamine system in BDNF and control mice three days after a chronic alcohol regiment. We hypothesize that chronic ethanol will decrease endogenous BDNF and DA levels. Using the in vivo microdialysis and in vitro voltammetry we will characterize the dopamine system following 3 days of ethanol withdrawal. The impact of this research is to improve our knowledge of the molecular mechanism of alcohol abuse in an effort to develop better treatments and/or therapeutics.