Molecular Mechanisms of Alcohol Tolerance in Brain Neurons

描述(申请人提供)：在美国，大约有4000万人患有酒精成瘾，表现出无节制饮酒、酒精耐受和依赖的症状。人类痛苦的程度和经济损失都突显了对这种疾病进行合理和有效治疗的必要性。在普通人群中，酗酒的比例约为8%-10%，而在患有创伤后应激障碍(PTSD)的越南退伍军人中，这一比例据报道为60%-80%。严重的车祸、身体虐待或童年虐待也可能导致创伤后应激障碍。创伤后应激障碍患者的症状包括创伤应激源复发、重温创伤经历(S)、产生回避和麻木(心理社会孤立)，以及增强觉醒和焦虑。酒精通常被用作临时缓解创伤后应激障碍症状的方便的非处方药。然而，如果对酒精的抗焦虑(抗焦虑)作用产生耐受性，缓解创伤后应激障碍症状所需的酒精量可能会增加，从而导致酒精成瘾的发展以及与酒精滥用相关的器官损害。学习和适当应对外部恐惧的能力在哺乳动物中是一种非常保守的行为，存在着由前扣带回(ACC)、杏仁核、海马体和蓝斑组成的恐惧神经元回路。特别是，ACC在评估外部刺激和计划对这些刺激的适当反应方面发挥着作用。最近的证据表明，ACC的谷氨酸能传递对于恐惧学习和获得性恐惧反应都是至关重要的，ACC神经元的故障会增加外部恐惧刺激和夸大内部恐惧刺激，导致高度焦虑症状。我们发现，急性中等浓度的乙醇可以抑制ACC中的谷氨酸能传递，并且这些神经元在酒精暴露期间很容易产生急性功能耐受。我们假设乙醇对ACC神经元谷氨酸能传递的抑制在一定程度上介导了酒精的抗焦虑作用，而ACC神经元对酒精的耐受是通过NR2B NMDA受体介导的机制产生的。在目前的提案中，我们的目标是阐明在ACC神经元中介导酒精耐受的分子机制。如果我们的假设被证明是正确的，针对NMDA受体NR2B亚单位的药物可能对治疗酒精成瘾有用。 与公共健康相关：急性酒精耐受性是指在酗酒期间酒精的作用减弱的一种情况。这种耐受性被认为是由于大脑对乙醇的适应性反应。我发现兴奋性神经递质受体-NMDA受体可以对酒精产生耐受性，这种耐受性可能是酒精诱导的神经元损伤的结果。我建议测试NMDAR耐受是否也发生在两种兴奋性毒性神经元损伤的实验模型中，并测试三种新的神经保护药物以防止酒精耐受。如果实验成功，我们可能会有治疗酒精成瘾的新药。

DESCRIPTION (provided by applicant): Approximately 40 million people in the US suffer from alcohol addiction exhibiting symptoms of uncontrolled alcohol drinking, alcohol tolerance and dependence. The degree of human suffering and economic loss both underscore the need for rational and effective treatments for this disorder. While the rate of alcohol abuse is about 8-10% in the general population, this rate is reported to be 60-80% among Vietnam veterans that suffer from post-traumatic stress disorder (PTSD). PTSD could also arise from severe automobile accidents, physical abuse, or childhood abuse. The PTSD sufferers exhibit symptoms that include recurrence of traumatic stressors, reliving the traumatic experience(s), developing avoidance and numbing (psychosocial isolation), as well as enhancing arousal and anxiety. Alcohol (ethanol) has often been used as a convenient over the- counter medication for temporary relief of PTSD symptoms. However, if tolerance to anti-anxiety (anxiolytic) effects of alcohol develops, the amount of alcohol required for the relief of PTSD symptoms may rise, contributing to the development of alcohol addiction as well as organ damages associate with alcohol abuse. The ability to learn and respond appropriately to external fear is a behavior that is well conserved in mammals, and there is a fear neuronal circuitry which consists of the anterior cingulate cortex (ACC), amygdala, hippocampus, and locus coeruleus. The ACC, in particular, performs a role in assessing the external stimuli and in planning an appropriate response to these stimuli. Recent evidence suggests that the glutamatergic transmission of the ACC is critical for fear learning and also for learned fear responding, and malfunctions of the ACC neurons would heighten external fear stimuli and exaggerate internal fear stimuli leading to high anxiety symptoms. We show that acute moderate concentrations of ethanol can inhibit glutamatergic transmission in the ACC, and that these neurons readily develop acute functional tolerance during ethanol exposure. We hypothesize that ethanol inhibition of glutamatergic transmission of the ACC neurons mediates in part the anxiolytic effects of alcohol, and that tolerance to these effects of alcohol is developed at the ACC neurons by the NR2B NMDA receptor-mediated mechanisms. In the present proposal, we aim to elucidate molecular mechanisms that mediate alcohol tolerance in the ACC neurons. If our hypotheses are proven correct, the drugs targeting NR2B subunit of the NMDA receptor may be useful in treating alcohol addiction. PUBLIC HEALTH RELEVANCE: Acute ethanol tolerance describes a condition where ethanol's effects are reduced during an episode of ethanol binge drinking. This tolerance is believed to be due to adaptive responses of the brain to ethanol. I discovered that excitatory neurotransmitter receptors - NMDA receptors can become tolerant to ethanol and this tolerance may be a result of ethanol-induced neuronal damage. I propose to test whether NMDAR tolerance also occurs in two experimental models of excitotoxic neuronal damage and also to test three new neuroprotective drugs to prevent ethanol tolerance. If the experiments are successful, we could have new medications for treating alcohol addiction.