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.

项目摘要 重度抑郁症（MDD）和酒精使用障碍（AUD）是共病。急性酒精会降低 类似焦虑和抑郁的行为长期饮酒会增加这两种负面情绪- 比如行为事实上，数十年的流行病学数据表明，个人使用酒精来缓解 消极情感状态负面情绪状态是否是由于MDD或反复酒精暴露 (AUD)研究人员现在开始研究最初是积极和有益的机制是如何产生的， 在戒断过程中转向负面情绪/快感缺乏。例如，我们对神经系统的 神经回路和神经递质/肽系统的基础上的急性和慢性影响的酒精对焦虑样 行为。令人惊讶的是，很少有人关注消极情感（快感缺失） 成分我们的临床前工作表明，急性乙醇治疗产生抗抑郁样作用 并劫持与NMDAR拮抗剂相同的生化途径。对乙醇和NMDAR的反应 拮抗剂的抗抑郁疗效是RNA结合蛋白脆性X金属蛋白的动态表达 阻滞蛋白（FMRP）。FMRP表达的减少使得跨突触的神经元表达上调。 促进新突触形成和抗抑郁作用的蛋白质。符合从 积极到消极的情绪样行为，FMRP在乙醇依赖性戒断过程中上调， 动物利用分子、生物化学和电生理学技术，结合一种新的突触 我们在实验室开发的检测分析（DetectSyn），以及我们的合作者在 Weiner实验室在酒精依赖的临床前模型中，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mRNA的结合，调节突触蛋白的合成， 这些靶向mRNA并促进新突触的形成。此外，在具体目标2中，我们将确定 在WD/负面影响期间，FMRP调节的抗抑郁剂信号通路被减弱或抑制 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FMRP靶mRNA，这些mRNA在WD期间被抑制，但在WD期间被释放。 由于在WD期间用急性乙醇治疗。使用计算/基因组方法，如文库 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，重新用途的FDA批准的药物， 治疗AUD和MDD。这些研究将为今后的药物干预治疗奠定基础 在酒精依赖的MDD共病个体中，WD期间的负面影响。