GSK3beta signaling in cocaine reward and memory

可卡因奖赏和记忆中的 GSK3beta 信号传导

基本信息

批准号：
9401843
负责人：
ELLEN M UNTERWALD
金额：
$ 39.63万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9401843
关键词：
Address Amygdaloid structure Anatomy Attenuated Behavior Biological Preservation Brain region Cocaine Cocaine Dependence Complex Compulsive Behavior Coupled Cues Data Development Disease Dopamine Dopamine Receptor Dorsal Drug Addiction Environment Exposure to Female Food Genetic Glutamate Receptor Glycogen Synthase Kinases Goals Hippocampus (Brain)Hyperactive behavior Individual Investigation Knock-out Lead Learning LoxP-flanked allele Maintenance Mediating Mediator of activation protein Memory Modeling Molecular Mus Neuronal Plasticity Neurons Nucleus Accumbens Palate Pathway interactions Pharmaceutical Preparations Physiological Play Positioning Attribute Procedures Process Publishing Relapse Research Rewards Role Self Administration Sex Characteristics Signal Pathway Signal Transduction Site Testing addiction brain cell cell type classical conditioning cocaine exposure cocaine relapse prevention craving cue reactivity disorder later incidence prevention drug craving genetic approach inhibitor/antagonist interdisciplinary approach loss of function male memory process mouse model new therapeutic target novel strategies novel therapeutics pre-clinical preclinical study preference relating to nervous system response treatment strategy

项目摘要

Compulsive drug-seeking and drug-taking behaviors are the hallmark of addiction, and these behaviors continue despite intense negative consequences to the individual. Maladaptive conditioned learning processes, together with molecular and cellular plasticity, play major roles in the development of this compulsive behavior. Addictive drugs including cocaine engage molecular signaling pathways that are involved in associative learning processes. Once learned, exposure to cues previously associated with cocaine can lead to conditioned physiological responses that are accompanied by intense drug craving which can trigger relapse. Hence, a goal of addiction treatment is to break the associations between previously learned positive subjective effects of cocaine and environmental cues that signal cocaine availability. In order to achieve this goal, detailed information is needed about the circuitry and molecular signaling within that circuitry that serves to reinforce and strengthen cocaine reward contextual memories. Glycogen synthase kinase-3beta (GSK3b) is uniquely positioned to regulate neuronal function and plasticity. It is important in dopamine-mediated behaviors and in memory processes, and GSK3 activity is required for cocaine-induced conditioned reward, hyperactivity, and locomotor sensitization. Relevant to relapse, GSK3b is activated by exposure to an environment previously paired with cocaine and, importantly, inhibition of GSK3b activity after reactivation of cocaine memories can abolish a previously established cocaine place preference. This project will address the overall hypothesis that GSK3b signaling is necessary for cocaine-induced reward, neuroplasticity and the reconsolidation of cocaine-associated contextual memories. Using a conditional genetic deletion mouse model, the anatomical and cellular substrates where GSK3b mediates cocaine-induced conditioned reward will be elucidated. Components of the GSK3b signaling pathway that are necessary for cocaine reward and reconsolidation of cocaine memories will be investigated including the downstream effector of GSK3b, the mTORC1 complex. The anatomic substrates of importance for maintenance of cocaine memories will be studied with the focus on a circuit consisting of the dorsal hippocampus to basolateral amygdala to nucleus accumbens. An additional aim will be to extend the studies into a cocaine iv self-administration model in order to investigate if cocaine seeking behaviors can be abolished by inhibition of GSK3 after recall of cocaine memories. Little is known about how the processes governing maintenance of cocaine memories may differ between males and females and hence, investigation of sex differences is another goal of the project. Using these multidisciplinary approaches, we are positioned to reveal molecular mechanisms and pathways underlying cocaine reward, contextual memories, craving and relapse, with the potential of establishing GSK3b as a novel target for therapeutics to prevent relapse to cocaine seeking.

强迫性寻毒和吸毒行为是成瘾的标志，这些行为尽管给个人带来了严重的负面影响，但仍继续进行。适应不良的条件性学习过程，与分子和细胞的可塑性一起，在这种强迫行为的发展中发挥着重要作用。包括可卡因在内的成瘾药物会参与参与联想的分子信号传导途径学习过程。一旦学会，接触先前与可卡因相关的线索可能会导致条件性生理反应伴随着强烈的药物渴望，可能引发复发。因此，成瘾治疗的目标是打破先前习得的积极认知之间的关联。可卡因的主观影响和表明可卡因可用性的环境因素。为了实现这一目标为了实现目标，需要有关电路和该电路中分子信号传导的详细信息强化可卡因奖励的情境记忆。糖原合成酶激酶 3beta (GSK3b) 是具有独特的调节神经元功能和可塑性的作用。它对于多巴胺介导的行为很重要在记忆过程中，GSK3 活性是可卡因诱导的条件奖励、多动症、和运动敏化。与复发相关，GSK3b 通过暴露于环境而被激活之前与可卡因配对，重要的是，在可卡因重新激活后抑制 GSK3b 活性记忆可以消除先前建立的可卡因位置偏好。该项目将解决总体假设 GSK3b 信号传导对于可卡因诱导的奖赏、神经可塑性和重新巩固与可卡因相关的情境记忆。使用条件性基因缺失小鼠模型中，GSK3b 介导可卡因诱导的条件奖励的解剖和细胞底物将予以阐明。 GSK3b 信号通路的组成部分对于可卡因奖励和将研究可卡因记忆的重新巩固，包括 GSK3b 的下游效应子，即 mTORC1 复合物。对于维持可卡因记忆具有重要意义的解剖学基础是研究重点是由背侧海马到基底外侧杏仁核到核组成的回路伏隔核。另一个目标是将研究扩展到可卡因静脉注射自我给药模型，以便研究召回可卡因后是否可以通过抑制 GSK3 来消除可卡因寻求行为回忆。人们对可卡因记忆的维持过程有何不同知之甚少因此，调查性别差异是该项目的另一个目标。使用通过这些多学科方法，我们能够揭示分子机制和途径潜在的可卡因奖励、情境记忆、渴望和复发，具有建立 GSK3b 的潜力作为预防可卡因复发的治疗新靶标。