Biochemical Studies Underlying Acute Ethanol's Antidepressant-like effects during Withdrawal in a Preclinical Model of Ethanol Dependence

乙醇依赖临床前模型中戒断期间乙醇急性抗抑郁样作用的生化研究

• 批准号: 10595193
• 负责人: Kimberly Frances Raab-Graham
• 金额: $ 34.52万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595193
• 关键词: Abstinence; Acute; Alcohol consumption; Alcohol dependence; Alcohols; Anhedonia; Animals; Antidepressive Agents; Anxiety; Attention; Behavior; Behavioral; Binding; Binding Proteins; Biochemical; Biochemical Pathway; Bioinformatics; Brain Diseases; Chronic; Code; Communication; Complex; Data; Dendrites; Development; Electrophysiology (science); Emotional; Emotions; Ethanol; Ethanol dependence; FDA approved; FMR1; Female; Foundations; Future; Genetic Transcription; Genomic approach; Grant; Human; Immunoprecipitation; Individual; Influentials; Injections; Intervention; Intoxication; Knockout Mice; Knowledge; Laboratories; Libraries; Literature; Major Depressive Disorder; Mediating; Mental Depression; Mental Health; Messenger RNA; Methods; Modeling; Molecular; Motivation; Mus; N-Methylaspartate; National Institute on Alcohol Abuse and Alcoholism; Negative Reinforcements; Network-based; Neurobiology; Neurotransmitters; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Play; Positive Reinforcements; Pre-Clinical Model; Property; Protein Biosynthesis; Proteins; Publishing; RNA; RNA immunoprecipitation sequencing; RNA-Binding Proteins; Repression; Research; Research Personnel; Rewards; Rodent Model; Role; Signal Pathway; Signal Transduction; Signaling Protein; Strategic Planning; Synapses; System; Techniques; Testing; Up-Regulation; Withdrawal; Work; alcohol effect; alcohol exposure; alcohol prevention; alcohol risk; alcohol use disorder; antagonist; antidepressant effect; anxiety-like behavior; burden of illness; comorbidity; depressive symptoms; detection assay; detection method; disability; drinking; effective therapy; epidemiologic data; experimental analysis; male; negative affect; negative emotional state; neural circuit; new therapeutic target; novel; pharmacologic; pre-clinical; protein expression; synaptogenesis; transcriptome sequencing

PROJECT SUMMARY Major depressive disorder (MDD) and alcohol use disorder (AUD) are comorbid. Acute alcohol decreases both anxiety- and depressive-like behaviors. Chronic alcohol exposure increases both of these negative emotion- like behaviors. In fact, decades of epidemiological data suggest that individuals use alcohol to alleviate a negative affective state. Whether the negative emotional state is due to MDD or repeated alcohol exposure (AUD), researchers are now beginning to examine how mechanisms that are initially positive and rewarding shift toward negative affect/anhedonia during withdrawal. For example, much is known about the neural circuitry and neurotransmitter/peptide systems underlying acute and chronic effects of alcohol on anxiety-like behaviors. Surprisingly, much less attention has been directed at the negative affective (anhedonia) component. Our preclinical work suggests that acute ethanol treatment produces an antidepressant-like effect and hijacks the same biochemical pathway as NMDAR antagonists. Pivotal to ethanol and NMDAR antagonists’ antidepressant efficacy is the dynamic expression of the RNA-binding protein Fragile X Mental Retardation Protein (FMRP). Reduction in FMRP expression allows for the upregulation of transsynaptic proteins that promote new synapse formation and antidepressant-like effects. Consistent with a shift from positive to negative emotion-like behaviors, FMRP is upregulated during withdrawal in ethanol-dependent animals. Using molecular, biochemical, and electrophysiological techniques, combined with a novel synapse detection assay that we developed in our laboratory (DetectSyn), and the expertise of our collaborators in the Weiner laboratory in preclinical models of alcohol dependence, we will determine in Specific Aim 1 if acute ethanol regulates the binding of FMRP to transsynaptic mRNAs, regulates the synaptic protein synthesis of these target mRNAs, and promotes new synapse formation. Moreover, in Specific Aim 2 we will determine if the FMRP-regulated antidepressant signaling pathway is muted or suppressed during the WD/negative affect state, and if acute ethanol treatment can reverse the biochemical and behavioral depressive phenotypes. Furthermore, we will isolate and sequence FMRP target mRNAs that are repressed during WD but released due to treatment with acute ethanol during WD. Using a computational/genomic approach such as the Library of Integrated Network-Based Cellular Signatures – a method that has shown promise in AUD research – these data will facilitate future studies using these targets to predict effective, repurposed FDA-approved drugs to treat AUD and MDD. These studies will lay the foundation for future pharmacological intervention to treat negative affect during WD in alcohol-dependent individuals with comorbid MDD.

项目总结 重度抑郁障碍(MDD)和酒精使用障碍(AUD)并存。急性酒精可同时降低 焦虑和抑郁的行为。长期饮酒会增加这两种负面情绪-- 类似的行为。事实上，数十年的流行病学数据表明，个人使用酒精来缓解 消极的情感状态。负面情绪状态是由MDD或反复饮酒引起的 (AUD)，研究人员现在开始研究最初积极和有益的机制 在戒烟过程中转向消极情绪/快感缺失。例如，人们对神经的了解很多。 酒精对类焦虑症急性和慢性影响的回路和神经递质/肽系统 行为。令人惊讶的是，人们对负面情绪(快感缺乏症)的关注要少得多 组件。我们的临床前工作表明，急性乙醇治疗会产生类似抗抑郁药的效果。 并劫持了与NMDAR拮抗剂相同的生化途径。乙醇和NMDAR的关键 拮抗剂的抗抑郁作用是RNA结合蛋白脆性X的动态表达 迟滞蛋白(FMRP)。FMRP表达的减少允许跨突触的上调 促进新突触形成和抗抑郁药样作用的蛋白质。与从 从积极到消极的情绪样行为，FMRP在酒精依赖戒断过程中上调 动物。利用分子、生化和电生理技术，结合一种新的突触 我们在实验室(DetectSyn)开发的检测方法，以及我们的合作者在 在韦纳实验室的临床前酒精依赖模型中，我们将在特定目标1中确定是否急性 乙醇调节FMRP与跨突触mRNAs的结合，调节突触蛋白的合成 这些靶向mRNAs，促进新突触的形成。此外，在具体目标2中，我们将确定是否 在WD/负性影响过程中，FMRP调节的抗抑郁信号通路被沉默或抑制 状态，以及急性乙醇治疗是否可以逆转生化和行为抑郁表型。 此外，我们将分离和测序在WD期间被抑制但被释放的FMRP靶向mRNA 由于在WD期间用急性乙醇治疗。使用计算/基因组方法，如图书馆 集成的基于网络的蜂窝签名-一种在AUD研究中显示出希望的方法-这些 数据将有助于未来的研究，使用这些目标来预测有效的，FDA批准的改变用途的药物 治疗AUD和MDD。这些研究将为未来的药物干预治疗奠定基础。 伴有MDD的酒精依赖者WD期间的负性情绪。