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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结