Center for Genetic Studies of Drug Abuse in Outbred Rats

近交系大鼠药物滥用基因研究中心

• 批准号: 9793605
• 负责人: Paul J Meyer
• 金额: $ 35.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9793605
• 关键词: Abstinence; Address; Animal Model; Area; Automobile Driving; Behavior; Behavioral; Brain; Buffaloes; Candidate Disease Gene; Characteristics; Cocaine; Consumption; Development; Dissociation; Dopamine; Drug Exposure; Drug abuse; Drug usage; Exposure to; Funding; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genomic Segment; Genomics; Heritability; Hour; Human; Inbred Strain; Incentives; Individual; Individual Differences; Intake; Knowledge; Laboratories; Measurement; Measures; Midbrain structure; Modeling; Motivation; Neurobiology; Pattern; Pharmaceutical Preparations; Phenotype; Population; Procedures; Process; Quantitative Trait Loci; Rattus; Reporting; Rodent; Sampling; Self Administration; Sex Differences; Symptoms; Universities; Work; addiction; behavior influence; cocaine exposure; design; drug relapse; experience; genetic variant; genome wide association study; genome-wide; individual variation; neurogenetics; novel; psychologic; sex; therapeutic target; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT While many individuals are exposed to addictive drugs in their lifetimes, only a small percentage develop the patterns of drug-taking associated with addiction. It is therefore crucial to identify the genetic vulnerability factors that influence the transition from recreational to problematic drug use. Studies investigating the genetic basis of addiction often use rodent self-administration models to induce addiction-like symptoms. However, these paradigms differ in the patterns of drug-taking they produce. For example, in the long access (LgA) paradigm, rats self-administer a drug such as cocaine continuously for 6 hours or longer, and this paradigm produces escalation in drug intake over several sessions in a manner that is characteristic of addiction. In contrast, in the intermittent access (IntA) paradigm, rats' access to cocaine is restricted such that overall intake is limited, yet leads to “spiking” brain levels of cocaine thought to be characteristic of drug-taking during binges in humans. Despite the lower level of intake relative to LgA, IntA results in larger increases in the motivational value of cocaine, as indicated by increases in the effort expended to acquire the drug, and relapse to drug- seeking after periods of abstinence. Thus, the scientific premise of this proposal is that the behavioral and neurogenetic processes driving drug- taking in these models are distinct, and comparing these processes in IntA versus LgA enable the dissociation of genes that promote escalation of intake from those that induced enhanced cocaine motivation (i.e., incentive sensitization). However, to date no studies have examined the genetic substrates of cocaine self- administration during the IntA paradigm, and no studies have compared transcriptomic changes induced by LgA and IntA. To fill these knowledge gaps and identify potentially therapeutic targets, we will conduct a genome-wide association study (GWAS) to determine the genetic variants that influence cocaine intake during IntA, and the degree to which IntA causes incentive sensitization, as measured by changes in progressive ratio breakpoint and cocaine self-administration despite negative consequences (footshock). Further, a unique feature of this application is that we have carefully designed our procedure to parallel an ongoing GWAS (U01DA043799) being conducted by Drs. Olivier George and Abraham Palmer, which allows us to use genetic correlations to compare IntA vs LgA, addressing a unique question: to what extent are the genes that influence the development of addiction-like behavior with LgA similar/different than with IntA? Finally, we will use RNA sequencing to compare how transcriptomic profiles are altered by drug exposure during IntA and LgA, enabling us to determine which gene networks are associated with (1) escalation of intake during LgA vs IntA, (2) incentive sensitization during IntA, and (3) compulsive drug intake during IntA and LgA.

项目总结/摘要 虽然许多人在一生中接触到成瘾药物，但只有一小部分人会发展成 与成瘾有关的吸毒模式。因此，确定遗传脆弱性至关重要 影响从娱乐性吸毒过渡到问题性吸毒的因素。研究调查遗传 成瘾基础常采用啮齿类动物自我给药模型诱导成瘾样症状。然而，在这方面， 这些范式的不同之处在于它们产生的吸毒模式。例如，在长存取（LgA）中， 在一个范例中，大鼠连续6小时或更长时间自我施用药物如可卡因，并且该范例 在几个疗程中以成瘾的特征方式产生药物摄入量的增加。在 相反，在间歇性接触（IntA）范式中，大鼠对可卡因的接触受到限制，使得总体摄入量 虽然是有限的，但会导致大脑中可卡因水平的“飙升”，这被认为是狂欢期间吸毒的特征。 在人类身上。尽管摄入水平相对于LgA较低，但IntA导致动机增加较大， 可卡因的价值，如获得毒品所花费的努力增加和复吸毒品所表明的， 寻求禁欲期 因此，这一建议的科学前提是，行为和神经遗传过程驱动药物- 采用这些模型是不同的，并且将IntA与LgA中的这些过程进行比较可以实现解离 促进摄入量增加的基因与诱导增强可卡因动机的基因（即，激励 致敏）。然而，到目前为止，还没有研究检查可卡因自身的遗传底物。 在IntA范例期间施用，并且没有研究比较由IntA范例诱导的转录组学变化。 LgA和IntA。 为了填补这些知识空白，并确定潜在的治疗靶点，我们将进行全基因组 关联研究（GWAS），以确定在IntA期间影响可卡因摄入的遗传变异， IntA导致激励敏感化的程度，通过累进比率断点的变化来衡量 和可卡因自我给药，尽管有负面后果（脚震）。此外，该系统的一个独特特征是 应用程序是我们精心设计了我们的程序，以并行正在进行的GWAS（U 01 DA 043799） 由Olivier乔治博士和Abraham Palmer博士进行，这使我们能够利用遗传相关性， 比较IntA与LgA，解决一个独特的问题：在多大程度上是基因的影响， LgA成瘾样行为的发展与IntA相似/不同？最后，我们将使用RNA 测序以比较IntA和LgA期间药物暴露如何改变转录组学谱， 我们确定哪些基因网络与（1）LgA与IntA期间摄入量的增加有关，（2） IntA期间的激励敏感化;（3）IntA和LgA期间的强迫性药物摄入。