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: 10686229
• 负责人: PIETRO P SANNA
• 金额: $ 21.49万
• 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/10686229
• 关键词: ATP1A2 gene; Abstinence; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animals; Automobile Driving; Behavior; Behavioral; Bioinformatics; Brain; Candidate Disease Gene; 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; Stimulus; Testing; Tetanus Helper Peptide; Training; Transgenic Organisms; alcohol abuse therapy; alcohol craving; alcohol cue; alcohol seeking behavior; alcohol use disorder; cellular targeting; craving; cue reactivity; design; drug of abuse; functional adaptation; gene induction; inducible Cre; insight; neural; neural patterning; new therapeutic target; problem drinker; prolonged abstinence; relapse prevention; single nucleus RNA-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.

项目概要 预防复发是治疗酒精使用障碍（酒精中毒）的一个主要目标，因为许多酗酒者 即使在成功戒酒一段时间后也能恢复饮酒。这种慢性复发的性质 人们认为，戒酒期间对酒精的渴望加剧会加剧酗酒。然而， 导致这种强化过程的大脑机制仍然未知。就像酒精引起的渴望一样 酗酒者康复过程中发出酒精信号的环境刺激（“酒精线索”）、线索引发的酒精寻求 已知大鼠在禁欲期间会加剧。我们发现酒精“提示反应”神经元（表达 伏隔核 (NAc) 核心的激活标记 Fos) 驱动这种行为强化，从而 将这些神经元识别为与提示引起的酒精寻求功能相关的细胞目标。我们还发现 这些“提示反应”神经元在禁欲期间经历独特的转录适应（包括那些 与酒精中毒/药物成瘾有关），这与邻近的“非反应性”神经元的适应有很大不同。 虽然这些结果提供了特定于行为功能神经单元的基因靶标，但我们到目前为止 在经过良好自我管理训练的大鼠中发现了这种适应（相对较短的禁欲期） 酒精，但没有接受导致身体依赖的程序。这些“不依赖”的老鼠会 因此，可能是“随意饮酒者”的模型，但可能不是酗酒患者的模型。事实上，众所周知，酗酒者 与不依赖饮酒的人相比，他们报告了更大的提示引发的渴望，并表现出不同的神经提示模式 反应性。同样，有或没有身体依赖史的老鼠在提示引发的酒精寻求中也是如此。 已知由不同的大脑机制控制。然而，目前尚无研究对禁欲进行表征： 导致有依赖史的动物对酒精的渴求加剧。因此我们接下来使用慢性 间歇性酒精蒸气暴露诱发身体依赖，发现酒精依赖大鼠 与不依赖酒精的人相比，表现出更多的由线索引发的酒精寻求行为和更大的强化行为 长期禁欲期间的老鼠。因此，这些“依赖”的老鼠可能会更好地模拟 与“非依赖性”大鼠相比，酗酒者在康复过程中对酒精的渴望更高，从而提供了更多的转化见解 酒精中毒的慢性复发性质。基于上述前提，本次R21项目将测试 中心假设是“NAc 核心驱动中酒精线索反应神经元特有的转录适应” 长期处于酒精依赖状态的大鼠中，线索引发的酒精寻求行为加剧 我们将使用神经活动特异性转录分析（目标 1）和基因拯救（目标 2）来 选择性地针对酒精“提示反应性”神经元，而不是“非反应性”神经元。结果将决定哪一个 转录适应在功能上与依赖大鼠的酒精寻求强度有关 长期禁欲。这些知识可能有助于确定开发新的治疗靶点 抗复发药物，以对抗酗酒者康复过程中日益强烈的酒精渴望。