Transcriptional adaptations driving the intensification of alcohol-seeking in dependent rats undergoing prolonged abstinence

转录适应导致长期戒酒的依赖性大鼠对酒精的渴求加剧

• 批准号: 10540014
• 负责人: PIETRO P SANNA
• 金额: $ 25.52万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540014
• 关键词: ATP1A2 gene; Abstinence; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animals; Automobile Driving; Behavior; Behavioral; Bioinformatics; Brain; Candidate Disease Gene; Cell Nucleus; Chronic; Cues; DRD2 gene; Dependence; Development; Down-Regulation; Drug Addiction; Exposure to; Future; Gene Expression Profiling; Gene Silencing; Gene Targeting; Genes; Genetic Transcription; Goals; Knowledge; Link; Modeling; Nature; Neurons; Nucleus Accumbens; Patients; Pharmaceutical Preparations; Phenotype; Physical Dependence; Procedures; Process; Rattus; Recording of previous events; Relapse; Reporting; Self Administration; Signal Transduction; Small Interfering RNA; Small Nuclear RNA; Stimulus; Testing; Tetanus Helper Peptide; Training; Transgenic Organisms; alcohol abuse therapy; alcohol craving; alcohol cue; alcohol seeking behavior; alcohol use disorder; base; cellular targeting; craving; cue reactivity; design; disorder later incidence prevention; drug of abuse; functional adaptation; gene induction; insight; neural patterning; new therapeutic target; non-alcoholic; problem drinker; relating to nervous system; transcriptome sequencing; vapor

PROJECT SUMMARY Relapse prevention is a major goal in the treatment of alcohol use disorder (alcoholism), as many alcoholics return to alcohol use even after a prolonged period of successful abstinence. This chronically relapsing nature of alcoholism is thought to be exacerbated by the intensification of alcohol craving during abstinence. However, the brain mechanism causing this intensification process remains unknown. Like alcohol craving provoked by environmental stimuli signaling alcohol (‘alcohol cues’) in recovering alcoholics, cue-provoked alcohol seeking in rats is known to intensify during abstinence. We have found that alcohol ‘cue-reactive’ neurons (expressing the activation marker Fos) in the nucleus accumbens (NAc) core drive this behavioral intensification, thereby identifying these neurons as cellular targets functionally linked to cue-provoked alcohol seeking. We also found that these ‘cue-reactive’ neurons undergo unique transcriptional adaptations during abstinence (including those linked to alcoholism/drug addiction) that are largely distinct from adaptations in adjacent ‘non-reactive’ neurons. While these results provide gene targets specific to behaviorally functional neural units, we have so far identified such adaptations (across relatively short abstinence) in rats that were well-trained to self-administer alcohol but were not subjected to physical dependence-inducing procedures. These ‘non-dependent’ rats will thus likely model ‘casual drinkers’ but perhaps not patients with alcoholism. Indeed, alcoholics are known to report greater cue-provoked craving than non-dependent drinkers and show different patterns of neural cue- reactivities. Similarly, cue-provoked alcohol seeking in rats with or without a history of physical dependence is known to be controlled by different brain mechanisms. However, no study has yet characterized abstinence- induced intensification of alcohol seeking in animals with dependence histories. We thus next used chronic intermittent alcohol vapor exposures to induce physical dependence and found that alcohol dependent rats show greater cue-provoked alcohol seeking and greater intensification of this behavior than non-dependent rats during prolonged abstinence. These ‘dependent’ rats will thus likely better model the intensification of alcohol craving in recovering alcoholics than ‘non-dependent’ rats, thereby providing more translational insights into the chronically relapsing nature of alcoholism. Based on the premise above, this R21 project will test the central hypothesis that “transcriptional adaptations unique to alcohol cue-reactive neurons in NAc core drive the intensification of cue-provoked alcohol seeking in alcohol dependent rats undergoing prolonged abstinence”. We will use neural activity-specific transcriptional profiling (Aim 1) and gene rescuing (Aim 2) to selectively target alcohol ‘cue-reactive’ – rather than ‘non-reactive’ – neurons. The results will determine which transcriptional adaptations are functionally linked to the intensification of alcohol seeking in dependent rats undergoing prolonged abstinence. Such knowledge may help identify novel therapeutic targets for developing anti-relapse medication to counter intensifying alcohol craving in recovering alcoholics.

项目摘要 预防复发是治疗酒精使用障碍（酒精中毒）的主要目标，因为许多酗酒者 即使在长时间成功戒酒后，也会恢复饮酒。这种慢性复发的本性 人们认为，戒酒期间对酒精的渴望加剧会加剧酒精中毒。然而，在这方面， 导致这种强化过程的大脑机制仍然未知。就像酒精的渴望， 环境刺激信号酒精（'酒精线索'）在恢复酗酒者，线索引起的酒精寻求 在大鼠中的作用在禁欲期间会增强。我们已经发现，酒精“线索反应”神经元（表达 在丘脑核（NAc）核心中的激活标志物Fos）驱动这种行为强化，从而 将这些神经元识别为功能上与线索激发的酒精寻求相关的细胞靶点。我们还发现 这些“线索反应”神经元在禁欲期间经历了独特的转录适应（包括那些 与酒精中毒/药物成瘾有关），这在很大程度上不同于邻近的“非反应性”神经元的适应。 虽然这些结果提供了特定于行为功能神经单元的基因靶点，但到目前为止， 在经过良好训练的大鼠中发现了这种适应（在相对较短的禁欲期内）， 酒精，但没有受到身体依赖诱导程序。这些“不依赖”的老鼠将 因此可能是“随意饮酒者”的模型，但可能不是酗酒患者。事实上，众所周知，酗酒者 比非依赖性饮酒者报告更大的线索引发的渴望，并显示出不同的神经线索模式- 反应性同样，在有或没有身体依赖史的大鼠中， 它们由不同的大脑机制控制。然而，还没有研究表明禁欲的特征- 在有依赖史的动物中诱导酒精寻求的强化。因此，我们接下来使用慢性 间歇性酒精蒸汽暴露诱导身体依赖，发现酒精依赖大鼠 显示出更大的线索引起的酒精寻求和更大的这种行为的强化比非依赖 长期禁欲的老鼠因此，这些“依赖性”大鼠可能会更好地模拟 酒精渴望在恢复酗酒者比'非依赖'大鼠，从而提供更多的翻译见解 酗酒的慢性复发性基于上述前提，此R21项目将测试 中心假设，“转录适应独特的酒精线索反应神经元在NAc核心驱动 酒精依赖大鼠长时间饮酒后线索诱发的酒精寻求强化 禁欲”。我们将使用神经活性特异性转录谱分析（Aim 1）和基因拯救（Aim 2）， 选择性地针对酒精“线索反应”-而不是“非反应”-神经元。结果将决定 转录适应在功能上与依赖大鼠酒精寻求的强化有关 长期禁欲这些知识可能有助于确定新的治疗靶点， 抗复吸药物，以对抗正在康复的酗酒者对酒精的渴望。