Molecular Mechanisms of Alcohol Tolerance in Brain Neurons

脑神经元酒精耐受的分子机制

• 批准号: 7989586
• 负责人: PO HSIUNG WU
• 金额: $ 22.71万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989586
• 关键词: Acute; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Anisomycin; Anterior; Anti-Anxiety Agents; Anxiety; Apoptotic; Arousal; Behavior; Behavioral; Brain; Brain Injuries; Caspase Inhibitor; Cessation of life; Child Abuse; Cognitive; Complex; Corpus striatum structure; Cycloheximide; Data; Dependence; Development; Disease; Dose; Drug Delivery Systems; Drug Tolerance; Economics; Ethanol; Exhibits; Experimental Models; Failure; Family; Fright; Gated Ion Channel; General Population; Glucose; Glutamates; Hippocampus (Brain); Human; Individual; Knock-out; Lead; Learning; Mammals; Mediating; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; NR2B NMDA receptor; Neurons; Neuroprotective Agents; Neurotransmitter Receptor; Organ; Oxygen; Pathway interactions; Pharmaceutical Preparations; Physical Dependence; Post-Traumatic Stress Disorders; Procedures; Protein Synthesis Inhibitors; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Protein Tyrosine Phosphatase Gene; Proteins; Recurrence; Reporting; Resistance; Role; Signal Pathway; Slice; Stimulus; Symptoms; System; Testing; Translating; Veterans; Vietnam; alcohol effect; alcohol exposure; attenuation; automobile accident; base; binge drinking; calmodulin-dependent protein kinase II; calpain inhibitor; cingulate cortex; deprivation; effective therapy; excitotoxicity; experience; in vitro Model; inhibitor/antagonist; locus ceruleus structure; mutant; neuronal circuitry; neurotransmission; phosphatase inhibitor; physical abuse; prevent; psychosocial isolation; public health relevance; research study; response; stressor; transmission process

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.

描述（由申请人提供）：美国约有4000万人患有酒精成瘾，表现出不受控制的饮酒、酒精耐受和依赖的症状。人类痛苦和经济损失的程度都突出表明，需要对这种疾病进行合理和有效的治疗。虽然酒精滥用率在一般人群中约为8-10%，但据报道，在患有创伤后应激障碍（PTSD）的越南退伍军人中，这一比率为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。PTSD患者表现出的症状包括创伤性应激源的复发，重温创伤经历，发展回避和麻木（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，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）作用的耐受性发展，那么缓解PTSD症状所需的酒精量可能会增加，从而导致酒精成瘾以及与酒精滥用相关的器官损伤的发展。学习和对外部恐惧做出适当反应的能力是哺乳动物中非常保守的行为，并且存在由前扣带皮层（ACC）、杏仁核、海马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作用。最近的证据表明，前扣带回的神经元传递对于恐惧学习和习得性恐惧反应至关重要，前扣带回神经元的功能障碍会增强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中的神经递质传递，并且这些神经元在乙醇暴露期间容易产生急性功能耐受。我们推测，酒精抑制ACC神经元的神经递质传递部分介导了酒精的抗焦虑作用，而对酒精这些作用的耐受性是由NR 2B NMDA受体介导的机制在ACC神经元产生的。在本研究中，我们的目标是阐明ACC神经元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，那么针对NMDA受体NR 2B亚基的药物可能对治疗酒精成瘾有用。 公共卫生关系：急性乙醇耐受性描述了在乙醇狂饮期间乙醇的作用降低的情况。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受体可以对乙醇产生耐受性，这种耐受性可能是乙醇诱导的神经元损伤的结果。我建议测试是否NMDAR耐受性也发生在两个实验模型的兴奋性神经元损伤，并测试三种新的神经保护药物，以防止乙醇耐受性。如果实验成功，我们可能会有治疗酒精成瘾的新药物。