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.

项目摘要 预防复发是治疗酒精疾病（酒精中毒）的主要目标，因为许多酒精中毒 即使长期成功的禁欲，恢复饮酒也是如此。这种长期传播的性质 酗酒被认为会因戒酒期间的渴望加剧而加剧。然而， 引起这种强化过程的大脑机制仍然未知。就像渴望的饮酒 环境刺激信号酒精（“酒精提示”）在恢复酒精中毒时，提示饮酒寻求酒精 在戒酒期间，已知在大鼠中会加剧。我们发现酒精“提示反应”神经元（表达 伏隔核（NAC）核心的激活标记物驱动此行为强化，从而 将这些神经元识别为与提示发动的酒精寻求相关的细胞靶标。我们还发现 这些“提示反应”神经元在禁欲期间经历了独特的转录改编（包括 与酒精中毒/药物成瘾有关的），这与相邻“无反应性”神经元的适应大大不同。 尽管这些结果提供了针对行为功能性神经单位的基因靶标的 在训练有素的自我管理的大鼠中确定了这种适应性（跨越相对较短的禁欲） 酒精但未受到物理依赖性程序的约束。这些“非依赖”大鼠将 这种可能的模型“随意饮酒者”，但也许不是酒精中毒的患者。确实，酗酒者已知 报告比非依赖性饮酒者更大的提示渴望，并显示出不同的神经提示模式 重复性。同样，在有或没有身体依赖史的大鼠中寻求提示的酒精是 已知由不同的大脑机制控制。但是，尚无研究表征戒酒 - 在具有依赖史的动物中诱发的饮酒诱导。因此，我们接下来使用了慢性 间歇性酒精蒸气暴露以诱导身体依赖，发现酒精依赖大鼠 与非依赖性相比，显示出更大的提示性酒精寻求和对这种行为的强化 长时间戒酒期间的大鼠。因此，这些“依赖”大鼠可能会更好地建模 与“非依赖性”大鼠相比，酒精渴望恢复酗酒者，从而提供了更多的翻译见解 进入酒精中毒的长期传播性质。基于上面的前提，此R21项目将测试 中心假设是“ NAC核心驱动中酒精提示反应性神经元独有的转录适应 在接受育酒的大鼠中寻求提示的酒精的强化延长 戒酒”。我们将使用特定于神经活动的转录分析（AIM 1）和基因拯救（AIM 2） 有选择地靶向酒精“提示反应”，而不是“非反应性” - 神经元。结果将确定哪个 转录适应在功能上与依赖大鼠寻求酒精的强化有关 长期节制。这种知识可能有助于确定开发的新型治疗靶标 抗释放药物以抵抗恢复酗酒者的渴望加强酒精。