BDNF, Dopamine and Ethanol

描述（由候选人提供）：我的短期目标是获得一个终身教职的博士学位。授予大学。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产生的神经适应。为了了解酒精中毒所产生的神经适应，本实验室将使用活体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2000万人忍受酒精滥用，这导致每年约2000亿美元的损失。本研究有两个目的：（1）通过使用脑源性神经营养因子（BDNF）水平降低50%的小鼠（BDNF）来了解脑中BDNF和多巴胺之间的相互作用;（2）评估慢性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BDNF和多巴胺之间的不平衡是否会导致酒精滥用或保护大脑免受与成瘾过程相关的生化适应。大多数药物滥用;像乙醇一样，具有提高脑区域如尾状核-壳核和丘脑核中细胞外多巴胺水平的能力。这种多巴胺的释放被认为在滥用药物的刺激特性中起着重要作用。最近的证据表明BDNF能够调节多巴胺神经传递，但最直接的证据表明BDNF对多巴胺D3受体的控制。使用体内微透析，在对照小鼠和BDNF小鼠中在存在或不存在多巴胺D3受体激动剂的情况下评价细胞外多巴胺水平。接下来，体外伏安法实验将检查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小鼠的BDNF水平较低，多巴胺系统功能低下，导致倾向于喝更多的酒。第二个目标是评估慢性酒精治疗三天后BDNF和对照小鼠的多巴胺系统。我们假设慢性乙醇会降低内源性BDNF和DA水平。使用体内微透析和体外伏安法，我们将表征多巴胺系统后3天的乙醇撤出。这项研究的影响是提高我们对酒精滥用分子机制的认识，以开发更好的治疗和/或疗法。

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.