Relapse-suppressing neuronal ensembles in cocaine addiction

可卡因成瘾中抑制复发的神经元群

• 批准号: 8601922
• 负责人: Nobuyoshi Suto
• 金额: $ 23.69万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601922
• 关键词: Behavioral; Behavioral Paradigm; Brain; Brain Mapping; Chronic; Clinical Research; Clinical Trials; Cocaine; Cocaine Dependence; Cues; Data; Development; Disease; Dissociation; Elements; Extinction (Psychology); Foundations; Future; Genetic Techniques; Goals; Grant; Habits; Intake; Intervention; Investigation; Label; Lead; Learning; Link; Maps; Medial; Mediating; Methods; Molecular; National Institute of Drug Abuse; Nature; Neurobiology; Neurons; Neuropharmacology; Pharmaceutical Preparations; Pharmacogenetics; Prefrontal Cortex; Punishment; Rattus; Recording of previous events; Recruitment Activity; Regimen; Relapse; Research; Research Design; Rewards; Signal Transduction; Site; Specificity; Staining and Labeling; Stimulus; Techniques; Testing; Time; Training; addiction; base; cocaine relapse prevention; cocaine use; craving; design; disorder later incidence prevention; effective intervention; high reward; high risk; insight; neurobehavioral; neurochemistry; novel; novel therapeutics; pre-clinical research; public health relevance; relating to nervous system; research study; social; tool

DESCRIPTION (provided by applicant): Cocaine addiction is a chronic relapsing disorder characterized by compulsive cocaine use. Over the past few decades, NIDA has very actively supported clinical and preclinical research designed to understand the motivational and neurobiological impacts of factors capable of promoting cocaine seeking and craving. Unfortunately, most of the interventions (e.g., anti-craving medications) aimed to block these relapse- promoting factors have been proven to be ineffective in clinical trials. Therefore, we believe that it is critical to make a strategic shift to investigate the factors capable of suppresing (as opposed to promoting) cocaine seeking, craving and ultimately relapse. On this premise, we developed an "omission cue-induced suppression (OCIS) paradigm" in order to systematically evaluate the relapse-suppressing potential of cues signaling cocaine omission (unavailability) in rats with a cocaine history associated with compulsive cocaine use. The preliminary results demonstrate for the first time that omission cues are capable of suppressing addiction-like cocaine seeking. The fact that OCIS and extinction of cocaine seeking significantly differ at behavioral level (unlike OCIS, extinction is ineffective at suppressing the relapse-promoting capacity of cocaine availability cues and cocaine itself) leaves open the possibility that they als differ at neurobiological level. Using the OCIS paradigm as the base for the proposed experiments, this project will test the overarching hypothesis that the OCIS of addiction-like cocaine-seeking habit involves distinct neuronal ensembles within the reward circuit. In Specific Aim 1, Fos/NeuN double-label staining (an immunohistochemical tool to map "activated" neuronal ensembles) will be used to localize neuronal ensembles activated by omission cues. In Specific Aim 2, the Daun02 inactivation method (a novel pharmacogenetic technique to selectively disrupt Fos positive "activated" neurons) will be used to determine the neuronal ensembles within the medial prefrontal cortex mediating OCIS. In line with the scope of R21 applications, the proposed experiments are exploratory and developmental but possibly with high reward for several reasons. First, no study has yet systematically examined the brain mechanisms that suppress cocaine seeking in rats with a drug history associated with compulsive cocaine use. Second, the Daun02 inactivation method has not been applied to determine neuronal ensembles mediating any form of drug-seeking suppression. Importantly, this is the only method currently available to examine the behavioral contribution of specific neuronal ensembles. Third, nothing is known of the neurobiology of OCIS. In summary, the proposed project is designed to provide the groundwork for future systemic research to uncover the brain mechanisms underlying the robust relapse-suppressing potential of omission cues. Such investigation may lead to more effective interventions to treat the chronically relapsing nature of cocaine addiction.

描述（由申请人提供）：可卡因成瘾是一种以强迫性可卡因使用为特征的慢性复发障碍。在过去的几十年中，NIDA非常积极地支持临床和临床前研究，旨在了解能够促进可卡因寻求和渴望的因素的动机和神经生物学影响。不幸的是，旨在阻止这些复发因素的大多数干预措施（例如，反捕获药物）在临床试验中已被证明无效。因此，我们认为，进行战略转变以调查能够支持（而不是促进）可卡因寻求，渴望并最终复发的因素。在这个前提下，我们开发了一种“遗漏提示诱导的抑制（OCIS）范式”，以系统地评估具有与强迫性可卡因使用相关的可卡因史的大鼠中提示信号可卡因遗漏（不可用）的复发抑制潜力。初步结果首次证明了遗漏提示能够抑制类似成瘾的可卡因寻求。在行为水平上寻求可卡因的OCIS和灭绝（与OCI不同，灭绝在抑制可卡因可用性提示和可卡因本身的复发能力方面无效的灭绝能力无效）留下了可能使它们在神经生物学水平上差异的可能性。将OCIS范式作为提出的实验的基础，该项目将测试总体假设，即成瘾的可卡因寻求可卡因习惯涉及奖励回路中不同的神经元合奏。在特定的目标1中，FOS/NEUN双标签染色（用于映射“激活”神经元集合的免疫组织化学工具）将用于通过遗漏提示激活的神经元合成。在特定的目标2中，DAUN02灭活方法（一种新型的药物遗传学技术，用于选择性破坏FOS阳性“激活”神经元）将用于确定内侧前额叶皮层介导OCI中的神经元集合。根据R21应用程序的范围，拟议的实验是探索性的和发展性的，但由于几个原因，可能具有很高的奖励。首先，尚未系统地检查抑制可卡因在具有强迫性可卡因相关的药物史的大鼠中寻求可卡因的大脑机制。其次，尚未应用DAUN02灭活方法来确定介导任何形式的寻求药物抑制的神经元集合。重要的是，这是目前可用于检查特定神经元集合的行为贡献的唯一方法。第三，关于OCI的神经生物学尚无任何人知道。总而言之，拟议的项目旨在为未来的系统研究提供基础，以揭示遗漏提示强大的复发潜力潜力的大脑机制。这种研究可能会导致更有效的干预措施，以治疗可卡因成瘾的长期复发性质。