Alcohol Use Disorder and Associated Neurological Symptoms of Cognitive Dysfunction and Pain

酒精使用障碍以及认知功能障碍和疼痛的相关神经系统症状

• 批准号: 10534684
• 负责人: Scott Edwards
• 金额: $ 4.72万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534684
• 关键词: Alcohol consumption; Alcohols; Area; Behavior; Behavioral; Brain; Central Nervous System; Characteristics; Chemosensitization; Chronic; Cognition; Cognitive; Cognitive deficits; Consumption; Data; Decision Making; Dendritic Spines; Disease; Disease Outcome; Disease Progression; Electrophysiology (science); Experimental Designs; Failure; Glucocorticoid Receptor; Glucocorticoids; Goals; HIV; HIV Infections; HIV-associated neurocognitive disorder; HIV/AIDS; Heavy Drinking; Human; Hyperalgesia; Impaired cognition; Impulsivity; Individual; Investigation; Link; Measures; Mental Depression; Modeling; Morphology; Motivation; Negative Reinforcements; Nervous System Trauma; Neuroanatomy; Neurobiology; Neurocognitive; Neurocognitive Deficit; Neurologic; Neurologic Deficit; Neurologic Symptoms; Neurons; Neuropathy; Nociception; Pain; Pathology; Patients; Peripheral; Peripheral Nervous System; Persons; Physical Function; Population; Positioning Attribute; Prefrontal Cortex; Process; Property; Psychosocial Factor; Receptor Signaling; Recurrent disease; Research; SIV; Short-Term Memory; Signal Transduction; Slice; Stress; Synapses; System; Techniques; Testing; United States; Virus Diseases; alcohol consequences; alcohol exposure; alcohol risk; alcohol use disorder; antiretroviral therapy; behavior measurement; chronic pain; depressive symptoms; drinking; emotional functioning; executive function; interest; negative affect; neuroadaptation; neuronal circuitry; nonhuman primate; pain sensitivity; pain symptom; preclinical study; psychiatric comorbidity; psychological distress; symptomatology; therapy adherence; western diet

Abstract LSUHSC CARC Research Component 3: Alcohol Use Disorder & Associated Neurological Symptoms of Cognitive Dysfunction and Pain Alcohol use disorder (AUD) is characterized by neurological deficits, negative affective states, and a profound escalation of drinking. The cognitive and behavioral deficits associated with excessive drinking are attributed to functional and persistent changes to neuronal circuitry. Chronic alcohol induced-cognitive impairments are associated with selective central nervous system damage in areas such as the prefrontal cortex (PFC). Excessive alcohol exposure also damages the peripheral nervous system to produce a characteristic neuropathy, and the resulting hyperalgesia (increased pain sensitivity) is hypothesized to potentiate negative reinforcement processes to increase motivation for alcohol. Alcohol use also represents a major exacerbating factor for human immunodeficiency virus (HIV) disease. Even in the post-antiretroviral therapy (ART) era neurocognitive deficits remain prevalent in persons living with HIV (PLWH). HIV-associated neurocognitive disorder (HAND) and co-occurring AUD can exacerbate these deficits. PLWH also suffer from chronic pain, which disrupts physical and emotional function, interferes with ART adherence, and doubles the chance of virologic failure. Pain symptoms in PLWH are associated with specific changes in the brain and correspondingly associates with numerous psychosocial factors in this population, including depression. While cognitive deficits and pain are closely linked in PLWH, few studies have examined the stress-related neurobiological factors that drive these interactions or how alcohol and HIV promote this process. The PFC represents and executes the highest forms of goal-directed behavior, and its function is compromised in motivational disorders such as AUD. As a potential neurobiological correlate of pain and cognitive impairment in PLWH, preclinical studies from our group and others have implicated a functional potentiation of glucocorticoid receptor (GR) signaling in association with excessive alcohol drinking, cognitive dysfunction, and chronic pain. Heightened GR signaling and altered excitability of vulnerable cognition- and pain-related brain areas such as the PFC may thus represent a unifying mechanism contributing to these pathologies. Finally, emerging evidence suggests that Western diets commonly consumed in the United States worsen both neurocognitive and pain symptomatology. Thus, the neurobiological interaction of excessive alcohol drinking, cognition, and pain in the context of Western diet consumption represents a critically underexplored area of HIV research in the public interest. Our overarching hypothesis is that excessive drinking and HIV/ART exposure in individuals consuming a Western diet additively produce cognitive deficits and hyperalgesia in PLWH in association with increased glucocorticoid signaling and hyperexcitability within the PFC. We will examine these factors using a bidirectional translational experimental design incorporating human and nonhuman primate models.

摘要LSUHSC CARC研究组件3：酒精使用障碍和相关神经系统 认知功能障碍和疼痛的症状 酒精使用障碍（AUD）的特征是神经系统缺陷，负面情感状态和深刻的特征 饮酒的升级。与饮酒过量相关的认知和行为缺陷归因于 神经元电路的功能和持续变化。慢性酒精引起的认知障碍是 与选择性中枢神经系统损害相关的区域，例如前额叶皮层（PFC）。 过多的酒精暴露还会损害周围神经系统以产生特征 神经病变和由此产生的痛觉过敏（疼痛敏感性增加）被认为增强了阴性 加强过程以增加酒精的动力。酒精使用也代表了一个严重的恶化 人类免疫缺陷病毒（HIV）疾病的因素。即使在抗逆转录病毒疗法（ART）时代 在患有艾滋病毒（PLWH）的人中，神经认知缺陷仍然普遍存在。与HIV相关的神经认知 障碍（手）和同时发生的AUD会加剧这些缺陷。 PLWH也患有慢性疼痛， 这会破坏身体和情感功能，干扰艺术的依从性，并使 病毒学衰竭。 PLWH中的疼痛症状与大脑的特定变化有关 在包括抑郁症在内的该人群中，与许多社会心理因素相关联。而认知缺陷 疼痛在PLWH中紧密相关，很少有研究检查与压力相关的神经生物学因素 推动这些相互作用，或者酒精和艾滋病毒如何促进这一过程。 PFC代表并执行 最高形式的目标指导行为及其功能在诸如AUD之类的动机疾病中受到损害。 作为PLWH疼痛和认知障碍的潜在神经生物学相关性，我们的临床前研究来自我们 组和其他人暗示了糖皮质激素受体（GR）信号传导的功能增强 与饮酒过多，认知功能障碍和慢性疼痛相关。 GR信号加剧 并改变了脆弱的认知和疼痛相关的大脑区域（例如PFC）的兴奋性可能代表 有助于这些病理的统一机制。最后，新兴的证据表明西方饮食 通常在美国消耗的会使神经认知和疼痛症状恶化。因此， 在西方饮食中，过度饮酒，认知和疼痛的神经生物学相互作用 出于公共利益，消费代表了艾滋病毒研究的一个急剧不足的领域。我们的总体 假设是，过度饮酒和艾滋病毒/艺术暴露在加上西方饮食的个人中 与糖皮质激素信号的增加和增加 PFC内的过度兴奋性。我们将使用双向翻译实验检查这些因素 设计结合了人类和非人类灵长类动物模型。