Center for Genetic Studies of Drug Abuse in Outbred Rats

项目摘要/摘要 虽然许多人在一生中都接触到令人上瘾的药物，但只有一小部分人会患上 与上瘾有关的吸毒模式。因此，确定遗传脆弱性是至关重要的。 影响从娱乐性药物使用过渡到问题药物使用的因素。对遗传基因的研究 成瘾的基础常采用啮齿动物自我给药模型来诱导成瘾样症状。然而， 这些范例在它们产生的吸毒模式上有所不同。例如，在长访问(LGA)中 范式，大鼠持续给药6小时或更长时间，这种范式 以一种上瘾的方式在几个疗程中导致药物摄入量的上升。在……里面 相比之下，在间歇性获取(INTA)范式中，大鼠获得可卡因的途径受到限制，以至于总摄入量 是有限的，但会导致大脑中被认为是狂欢期间吸毒的特征的可卡因水平“激增” 在人类身上。尽管与LGA相比，INTA的摄入水平较低，但INTA导致了动机的更大增长 可卡因的价值，如为获得该药物而花费的努力的增加所表明的，并重新吸食该药物- 在禁欲时期之后寻找。 因此，这一提议的科学前提是，驱动药物的行为和神经遗传过程- 接受这些模型是不同的，并将这些过程在INTA和LGA中进行比较，从而实现分离 从那些引起可卡因动机增强(即诱因)的基因中促进摄入量升级的基因 敏化)。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范式中给药，没有研究比较由 LGA和INTA。 为了填补这些知识空白并确定潜在的治疗靶点，我们将在全基因组范围内进行 关联研究，以确定在INTA期间影响可卡因摄入量的遗传变异，以及 INTA引起激励敏感化的程度，通过累进比率断点的变化来衡量 和不顾负面后果的可卡因自我管理(足击)。此外，这一点的一个独特特征 应用程序是，我们仔细设计了我们的程序，以并行正在进行的GWAS(U01DA043799) 由奥利维尔·乔治博士和亚伯拉罕·帕尔默博士主持，这使得我们能够利用遗传相关性来 比较INTA和LGA，解决一个独特的问题：在多大程度上影响 LGA与INTA相似/不同的成瘾性行为的发展？最后，我们将使用RNA 测序以比较在INTA和LGA期间药物暴露如何改变转录图谱，使 US确定哪些基因网络与(1)LGA与INTA期间摄入量增加有关，(2) INTA期间的激励性敏感化；(3)INTA和LGA期间的强制药物摄入。

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.