Traumatic stress and binge drinking as risk factors for excessive alcohol intake

创伤性压力和酗酒是过量饮酒的危险因素

• 批准号: 10554315
• 负责人: DEBORAH A. FINN
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554315
• 关键词: Agonist; Alcohol consumption; Alcohols; Animal Model; Anxiety; Area; Behavior; Behavioral; Biological; CRF receptor type 1; Classification; Corticotropin-Releasing Hormone; Cytosine; DNA Methylation; Data; Development; Disease; Economic Burden; Epigenetic Process; Ethanol; Euthanasia; Exhibits; Exposure to; Female; Funding; GPR39 gene; Gene Expression; Gene Expression Profiling; Genes; Glucocorticoid Receptor; Health; Heart Rate; Heavy Drinking; Heterogeneity; Hippocampus; Hospitalization; Human; Incidence; Intake; Link; Maps; Methylation; Military Personnel; Modeling; Molecular; Mus; Neurons; Nucleic Acid Regulatory Sequences; Nucleus Accumbens; Odors; Pathway interactions; Patients; Pattern; Pharmacological Treatment; Pharmacology Study; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prevalence; Prognosis; Proteins; Recovery; Recreation; Reporting; Risk; Risk Factors; Rodent; Role; Sex Differences; Signal Pathway; Signal Transduction; Stress; Subgroup; Symptoms; Testing; Time; Trauma; Validation; Veterans; Western Blotting; alcohol reward; alcohol use disorder; antagonist; anxiety-related behavior; behavioral outcome; behavioral response; binge drinking; comorbidity; conditioned place preference; drinking; effective therapy; genome-wide; glucocorticoid-induced orphan receptor; male; military veteran; neurosteroids; novel; receptor; resilience; response; sex; stressor; therapeutically effective; traumatic stress; treatment strategy; young adult

Post-traumatic stress disorder (PTSD) is classified as a trauma- or stressor-related disorder, and evidence confirms an association between PTSD and the development of an alcohol use disorder (AUD). Despite heterogeneity in the incidence of PTSD, high comorbidity of PTSD and AUD are reported in the veteran population. Furthermore, the exacerbation of symptoms in veterans with comorbid PTSD/AUD negatively influences recovery prognosis and effective therapeutic strategies. We and others found that exposure to predator odor stress (PS), used as an animal model of PTSD, significantly increases anxiety-related behaviors and subsequent alcohol (ethanol) intake in rodents. Most importantly, we observed heterogeneity in these behavioral responses, as is observed in human PTSD/AUD patients. Additionally, prior binge drinking (BD) produced a greater enhancement in ethanol drinking following intermittent PS in stress “sensitive” mice. Specifically, “PS-sensitive” male and female C57BL/6J (B6) mice exhibited > 70% increase in ethanol intake (> 2.5 g/kg over baseline), while ethanol intake was unchanged in “resilient” mice. Additional studies in B6 mice determined that BD alone produced sexually divergent changes in signaling pathways in the nucleus accumbens (NAC), while the enhanced ethanol intake following BD and PS produced sex differences in proteins related to the stress axis and neurosteroid synthesis in prefrontal cortex and hippocampus (NAC not examined in that study). In conjunction with evidence for separate behavioral and epigenetic adaptations underlying stress “sensitivity” and “resilience”, we hypothesize that: (1) distinct behavioral and molecular adaptations confer “sensitivity” and “resilience” to the enhancing effect of BD and PS on later ethanol drinking, (2) BD induces DNA methylation (DNAm) signals and associated changes in gene expression that alter adaptability to PS, and (3) sex differences exist in the underlying mechanisms in B6 mice. Aim 1 studies will determine whether “sensitivity” vs “resilience” to PS-enhanced drinking after prior BD is associated with altered anxiety-related behavior, heart rate (HR), and/or ethanol reward and whether sex differences exist in these relationships. Four groups will be tested: Group 1 (BD+4 weeks 23 h ethanol drinking with intermittent PS; divided into “sensitive” and “resilient” subgroups); Group 2 (intermittent PS only); Group 3 (naïve); Group 4 (BD only). After the post-PS drinking (Group 1), final PS (Group 2), or equivalent time point (Groups 3 & 4), HR and anxiety-related behavior will be assessed in one study and conditioned place preference will be tested in a separate study. Aim 2 will identify epigenetic signals and linked gene expression profiles in the NAC that confer “sensitivity” and “resilience” to PS-enhanced drinking after prior BD. Groups will be as in Aim 1, but mice will be euthanized following final BD, post-PS drinking, or final PS. We predict that the genome-wide DNAm analysis will identify differentially methylated cytosines and regions mapping to novel and mostly distinct but some shared genes, regulatory regions, and networks in males and females that will be associated with “sensitivity” and “resilience” to PS-enhanced drinking. DNAm and gene expression association analysis will be integrated with behavioral outcomes from Aim 1 to pinpoint targets for functional analysis. Aim 3 will confirm the functional role of selected genes (Aim 2) important for “sensitivity” and “resilience” to PS-enhanced drinking and associated behaviors. Protein levels will be confirmed by Western blots. Pharmacological studies will manipulate candidate molecules and determine the effect on PS-enhanced drinking, BD, anxiety, and HR, beginning with 3 molecules identified during current funding. Elucidating biological and molecular mechanisms that confer “sensitivity” and “resilience” to escalated ethanol drinking following BD and traumatic stress can guide pharmacological treatment strategies for AUD and PTSD, which likely differ in males and females and represent important areas of focus in the effective treatment of our veterans.

创伤后应激障碍(PTSD)被归类为创伤或应激源相关的障碍，有证据表明 证实了创伤后应激障碍与酒精使用障碍(AUD)的发展之间的联系。尽管 在退伍军人中，创伤后应激障碍发生率的异质性、创伤后应激障碍和AUD的高共患率被报道。 人口。此外，患有创伤后应激障碍/澳大利亚疾病的退伍军人的症状恶化呈负性 影响康复预后和有效的治疗策略。我们和其他人发现，接触到 捕食者气味应激(PS)被用作创伤后应激障碍的动物模型，显著增加焦虑相关行为 以及随后对啮齿动物的酒精(乙醇)摄入。最重要的是，我们观察到这些 行为反应，正如在人类PTSD/AUD患者中观察到的那样。此外，既往酗酒(BD) 在压力“敏感”的小鼠中，间歇性PS后，酒精饮用量有更大的增加。 具体地说，对PS敏感的雄性和雌性C57BL/6J(B6)小鼠的酒精摄入量增加了70%(&gt； (比基线高2.5克/公斤)，而“有弹性”的小鼠的乙醇摄入量没有变化。对B6小鼠的其他研究 确定BD单独导致了核内信号通路的性别分化变化 伏隔(NAC)，而BD和PS后乙醇摄入量增加导致性别差异 额叶皮质和海马区应激轴和神经类固醇合成相关蛋白质(NAC NOT) 在该研究中进行了审查)。结合分离的行为和表观遗传适应的证据 我们假设：(1)不同的行为和分子水平 适应赋予BD和PS对后期乙醇的增强作用的“敏感性”和“韧性” 饮酒，(2)BD诱导DNA甲基化(DNaM)信号和相关的基因变化 表达改变对PS的适应性；(3)潜在机制存在性别差异 在B6小鼠体内。目标1的研究将确定对PS增强的饮酒是否有“敏感性”和“韧性” 既往BD与焦虑相关行为、心率(HR)和/或酒精奖励和 这些关系中是否存在性别差异。将测试四个组：组1(BD+4周23小时 酒精饮用伴间歇性PS；分为“敏感”和“坚韧”两个亚组)；第2组 (仅限间歇性PS)；3组(幼稚)；4组(仅BD)。在PS后饮酒(第1组)后，最终PS (组2)或同等时间点(组3和组4)，HR和焦虑相关行为将被一次评估 研究和条件位置偏好将在另一项研究中进行测试。目标2将识别表观遗传信号 以及NAC中相关的基因表达谱，赋予PS增强的敏感性和韧性 既往BD后饮酒。分组将与目标1相同，但小鼠将在最后一次BD后、PS后被安乐死 饮酒，或最终PS。我们预测全基因组dNaM分析将识别差异甲基化 胞嘧啶和区域映射到新的且大多不同但一些共享的基因、调节区和 男性和女性对PS增强的“敏感性”和“恢复力”相关的网络 喝酒。DNaM和基因表达关联分析将与来自 目标1确定功能分析的靶点。目标3将确认选定基因(AIM)的功能作用 2)对PS增强的饮酒和相关行为的“敏感性”和“弹性”很重要。蛋白质水平 将通过Western blotts得到确认。药理学研究将操纵候选分子和 从确定的3个分子开始，确定PS对增强饮酒、BD、焦虑和心率的影响 在目前的资金支持下。阐明生物学和分子机制，赋予“敏感性”和 对BD和创伤应激后不断增加的酒精饮酒的适应能力可以指导 AUD和PTSD的药物治疗策略可能在男性和女性中有所不同 并代表了有效治疗退伍军人的重要重点领域。

项目成果

Dynamic Adaptation in Neurosteroid Networks in Response to Alcohol.

神经类固醇网络对酒精的动态适应。

• DOI: 10.1007/164_2017_82
• 发表时间: 2018
• 期刊: Handbook of experimental pharmacology
• 作者: Finn,DeborahA;Jimenez,VanessaA
• 通讯作者: Jimenez,VanessaA

Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice.

• DOI: 10.3389/fgene.2018.00325
• 发表时间: 2018
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Finn DA;Hashimoto JG;Cozzoli DK;Helms ML;Nipper MA;Kaufman MN;Wiren KM;Guizzetti M
• 通讯作者: Guizzetti M