Comorbidity of PTSD and Alcohol Dependence: Endocannabinoid Regulation

PTSD 和酒精依赖的共病：内源性大麻素调节

• 批准号: 10269001
• 负责人: Veronica Piggott
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269001
• 关键词: 2-arachidonylglycerol; Address; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Amygdaloid structure; Animal Behavior; Animals; Anterior; Anxiety; Attenuated; Award; Beds; Behavior; Behavioral; Biochemical; Brain region; C57BL/6 Mouse; CNR1 gene; CNR2 gene; Cannabinoids; Cell Nucleus; Cerebellum; Chronic; Chronic stress; Clinical Research; Consumption; Corpus striatum structure; Data; Dependence; Diagnosis; Distress; Dorsal; Endocannabinoids; Ethanol; Ethanol dependence; Exposure to; Female; Future; Health; Hippocampus (Brain); Immunohistochemistry; Individual; Intervention; Knowledge; Ligands; Liquid Chromatography; Marble; Mass Spectrum Analysis; Military Personnel; Mission; Modeling; Molecular; Motivation; Mus; Neurosciences; Nucleus Accumbens; Outcome; Outcome Measure; Pathway interactions; Patient Care; Play; Polymerase Chain Reaction; Post-Traumatic Stress Disorders; Prefrontal Cortex; Regulation; Rehabilitation therapy; Relapse; Research; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Stress; Symptoms; System; Techniques; Testing; Therapeutic; Time; Training; Translating; Ventral Tegmental Area; Veterans; Vietnam; Withdrawal; Withdrawal Symptom; acute stress; alcohol craving; alcohol effect; alcohol exposure; alcohol misuse; alcohol reinforcement; alcohol relapse; alcohol use disorder; anandamide; base; biological adaptation to stress; combat; comorbidity; drinking; efficacy evaluation; efficacy testing; functional outcomes; high risk; innovation; male; methanandamide; mouse model; programs; protein expression; psychological distress; psychological symptom; receptor; receptor expression; receptor function; tandem mass spectrometry; traumatic stress; vapor

Thirty-one percent of the Vietnam-era Veterans have been diagnosed with posttraumatic stress disorder (PTSD). Among those, 70% have also been diagnosed with an alcohol use disorder (AUD). Veterans with PTSD use alcohol to cope with their distressing psychological symptoms such as anxiety. However, alcohol withdrawal effects overlap with PTSD symptoms, thereby reinforcing alcohol consumption to alleviate the PTSD symptoms. Studies have shown that individuals with comorbid PTSD and AUD have increased intensity of alcohol cravings and relapse faster during withdrawal than those with AUD only. The cannabinoid (CB) system plays an important role in both stress and alcohol dependence. Clinical studies have shown that individuals with PTSD have dysregulated levels of the endocannabinoids, 2-arachidonolglycerol (2-AG) and anandamide (AEA). Animal studies have also shown that both 2-AG and AEA concentrations and CB1 receptor protein levels are altered after acute and chronic stress. While extensive research has shown that PTSD or AUD alone affects the CB system, and different durations of ethanol withdrawal alone dysregulate the CB1 receptor, the role of the CB system on the comorbidity of PTSD and alcohol dependence and withdrawal is yet unknown. This knowledge gap will be addressed in this application by elucidating the mechanism by which the comorbidity of PTSD and ethanol dependence and withdrawal dysregulates cannabinoid functions that cause negative health consequences outcomes for our Veterans. The central hypothesis of this project is that PTSD comorbid with ethanol dependence and withdrawal will uniquely dysregulate CB signaling causing an increase in ethanol consumption and anxiety behavior, and that a cannabinoidergic-based intervention will block this effect. Mice will undergo traumatic stress using the single prolonged stress paradigm followed by chronic intermittent ethanol vapor (CIEv) exposure, a model of ethanol dependence. After 4 cycles of CIEv with 5-days of 2-bottle choice drinking tests during intervening weeks, mice will be withdrawn from ethanol for 7, 30, and 60 days. The following three Specific Aims will be tested to support the central hypothesis: 1) Evaluate the effects of traumatic stress and ethanol dependence on ethanol consumption and anxiety behavior as a function of ethanol withdrawal duration. 2) Examine changes in CB signaling associated with ethanol-induced withdrawal behaviors as a factor of withdrawal duration. 3) Evaluate the efficacy of a selective CB1 agonist, methanandamide, to block stress-induced ethanol dependence and withdrawal outcomes.

百分之三十一的越战退伍军人被诊断患有创伤后应激障碍 （创伤后应激障碍）。其中，70% 的人还被诊断患有酒精使用障碍 (AUD)。患有创伤后应激障碍 (PTSD) 的退伍军人 使用酒精来应对焦虑等令人痛苦的心理症状。然而，酒精戒断 效果与 PTSD 症状重叠，从而加强饮酒以缓解 PTSD 症状。 研究表明，患有 PTSD 和 AUD 共病的个体对酒精的渴望程度更高 与仅使用澳元的患者相比，撤药期间复发速度更快。大麻素（CB）系统发挥着重要作用 在压力和酒精依赖中发挥作用。临床研究表明，患有 PTSD 的人 内源性大麻素、2-花生四烯酸甘油 (2-AG) 和花生四烯酸乙醇胺 (AEA) 水平失调。动物 研究还表明 2-AG 和 AEA 浓度以及 CB1 受体蛋白水平都会改变 急性和慢性应激后。虽然广泛的研究表明 PTSD 或 AUD 单独影响 CB 系统，以及不同持续时间的乙醇戒断单独使 CB1 受体失调，CB 的作用 PTSD 与酒精依赖和戒断共病的系统尚不清楚。 本申请将通过阐明该知识的机制来解决这一知识差距 PTSD 的共病和乙醇依赖和戒断会导致大麻素功能失调 对我们的退伍军人的健康造成负面影响。该项目的中心假设是 PTSD 与乙醇依赖和戒断共病将独特地失调 CB 信号，导致增加 乙醇消耗和焦虑行为，并且基于大麻素的干预措施将阻止这种情况 影响。 小鼠将使用单一的长期应激范式经历创伤性应激，然后是慢性应激 间歇性乙醇蒸气（CIEv）暴露，乙醇依赖模型。 4 个为期 5 天的 CIEv 周期后 在接下来的几周内进行 2 瓶选择饮酒测试时，小鼠将停止使用乙醇 7、30 和 60 天。将测试以下三个具体目标来支持中心假设： 1) 评估效果 创伤性应激和乙醇依赖对乙醇消耗和焦虑行为的影响 乙醇戒断持续时间。 2) 检查与乙醇诱导的戒断相关的 CB 信号变化 行为作为戒断持续时间的一个因素。 3) 评估选择性CB1激动剂的功效， 甲烷酰胺，阻止压力引起的乙醇依赖和戒断结果。

项目成果

Traumatic Stress, Chronic Ethanol Exposure, or the Combination, Alter Cannabinoid System Components in Reward and Limbic Regions of the Mouse Brain.

创伤性应激、慢性乙醇暴露或两者的组合，会改变小鼠大脑奖励区和边缘区的大麻素系统成分。

• 发表时间: 2021-04-06
• 作者: Piggott, Veronica M;Lloyd, Scott C;Matchynski, James I;Perrine, Shane A;Conti, Alana C
• 通讯作者: Conti, Alana C

Single-Prolonged Stress Impairs Prefrontal Cortex Control of Amygdala and Striatum in Rats.

单一长期压力会损害大鼠前额皮质对杏仁核和纹状体的控制。

• 发表时间: 2019
• 作者: Piggott, Veronica M;Bosse, Kelly E;Lisieski, Michael J;Strader, John A;Stanley, Jeffrey A;Conti, Alana C;Ghoddoussi, Farhad;Perrine, Shane A
• 通讯作者: Perrine, Shane A

Chronic Intermittent Ethanol Exposure Increases Ethanol Consumption Following Traumatic Stress Exposure in Mice.

慢性间歇性乙醇暴露会增加小鼠遭受创伤性应激后的乙醇消耗。

• 发表时间: 2020
• 作者: Piggott, Veronica M;Lloyd, Scott C;Perrine, Shane A;Conti, Alana C
• 通讯作者: Conti, Alana C