Molecular Mechanisms of Alcohol Tolerance in Brain Neurons

描述（由申请人提供）：在美国大约有4000万人患有酒精成瘾，表现出不受控制的饮酒、酒精耐受和酒精依赖的症状。人类痛苦和经济损失的程度都强调需要对这种疾病进行合理和有效的治疗。一般人群中酒精滥用率约为8-10%，而据报道，在患有创伤后应激障碍（PTSD）的越战老兵中，这一比例为60-80%。创伤后应激障碍也可能由严重的车祸、身体虐待或童年虐待引起。创伤后应激障碍患者表现出的症状包括创伤性压力源的复发，重新体验创伤性经历，形成回避和麻木（心理社会隔离），以及增强唤醒和焦虑。酒精（乙醇）经常被用作一种方便的非处方药物，用于暂时缓解创伤后应激障碍症状。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。哺乳动物对外部恐惧的学习和适当反应能力是一种保守的行为，并且存在由前扣带皮层（ACC）、杏仁核、海马体和蓝斑组成的恐惧神经回路。特别是，前扣带皮层在评估外部刺激和计划对这些刺激的适当反应方面发挥作用。最近的证据表明，前扣带皮层的谷氨酸能传递对恐惧学习和习得性恐惧反应至关重要，前扣带皮层神经元的功能障碍会增强外部恐惧刺激，放大内部恐惧刺激，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，并且这些神经元在乙醇暴露期间很容易产生急性功能耐受性。我们假设乙醇抑制ACC神经元的谷氨酸能传递在一定程度上介导了酒精的抗焦虑作用，并且ACC神经元对这些酒精作用的耐受性是通过NR2B NMDA受体介导的机制形成的。在目前的提议中，我们的目的是阐明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，靶向NMDA受体NR2B亚基的药物可能对治疗酒精成瘾有用。

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.