Cocaine omission cues suppress relapse: role of the medial prefrontal cortex

可卡因遗漏线索抑制复发：内侧前额叶皮层的作用

• 批准号: 9503832
• 负责人: Nobuyoshi Suto
• 金额: $ 1.87万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9503832
• 关键词: Acetylcholine; Automobile Driving; Behavioral Paradigm; Biological Assay; Brain; Chlorides; Choline O-Acetyltransferase; Chronic; Cocaine; Cocaine Dependence; Cues; Development; Disease; Drug Addiction; Fluoro-Gold; Glutamate Decarboxylase; Glutamate Receptor; Glutamates; Grant; High Pressure Liquid Chromatography; Immunohistochemistry; Intake; Interneurons; Label; Lesion; Medial; Mediating; Methods; Microdialysis; Molecular; Monitor; Nature; Neurobiology; Neurons; Nicotinic Receptors; Output; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Population; Prefrontal Cortex; Rattus; Recording of previous events; Relapse; Reporting; Research; Role; Sampling; Self Administration; Serotonin; Signal Transduction; Source; Stress; Techniques; Testing; Tracer; addiction; base; calmodulin-dependent protein kinase II; cholinergic; cocaine relapse; cocaine relapse prevention; cocaine use; cognitive control; craving; design; effective intervention; experimental study; extracellular; gamma-Aminobutyric Acid; improved; insight; nerve supply; neurobehavioral; neurochemistry; neurotransmission; novel; public health relevance; relating to nervous system

DESCRIPTION (provided by applicant): Cocaine addiction is a chronic relapsing disorder characterized by compulsive cocaine use. Significant effort has been dedicated to reveal neurobehavioral factors responsible for promoting craving and drug seeking. Despite such effort, effective interventions to prevent cocaine relapse have yet to be established. An alternative research strategy may thus prove beneficial. For this premise, an "omission cue-induced suppression (OCIS) paradigm" was developed to investigate the relapse-suppressing potential of cues that signal cocaine omission (unavailability) in rats with a history of compulsiv cocaine intake. Preliminary results indicate a novel finding that, despite the history of compulsive cocaine intake, omission cues suppress cocaine seeking triggered by all major modes of relapse-promotion (drug cues, stress and cocaine priming) as well as cocaine intake. Additional results indicate that omission cues induce Fos (a marker of neural activation) in a discrete subpopulation of neurons localized within the medial prefrontal cortex (mPFC) - a region implicated in cognitive control of cocaine craving. Importantly, selective disruption of omission cue-activated neurons in mPFC blocked the subsequent expression of OCIS. Thus, 1) omission cue-induced neural activation in mPFC mediates OCIS. Because neural activation is a product of local excitatory neurotransmission, OCIS is likely controlled by 2) omission cue-activated excitatory neurotransmission in mPFC, as well as 3) omission cue- activated excitatory afferent innervations to mPFC - brain substrates known to provide the drive to induce neural activation in mPFC. Considering the above, this project will test the overarching hypothesis that OCIS of cocaine seeking is controlled by omission cue-activated excitatory neurotransmission and afferents driving distinct neural activation in mPFC. Three Aims are proposed to establish the medial prefrontal cortical 1) neural phenotypes, 2) neurochemical signals and 3) neurocircuitry responsible for relapse-suppression by cocaine omission cues. Collectively, the expected results will establish brain mechanisms that actively suppress - rather than promote - cocaine relapse, and therefore present new insights for blocking relapse.

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。已经致力于揭示负责促进渴望和寻求药物的神经行为因素。尽管付出了这样的努力，但尚未建立有效的防止可卡因复发的干预措施。因此，另一种研究策略可能证明是有益的。为此，开发了“遗漏提示诱导的抑制（OCIS）范式”，以研究在具有强迫性可卡因摄入量病史的大鼠中可卡因遗漏（无法可用）的提示的复发潜力。初步结果表明，尽管有强迫性可卡因摄入量的历史，但遗漏提示抑制了可卡因，从所有主要的复发促进方式（药物提示，压力，压力和可卡因启动）以及可卡因摄入触发的寻求可卡因以及可卡因。其他结果表明，遗漏提示在内部内侧前额叶皮层（MPFC）中的神经元的离散亚群中诱导FOS（神经激活的标志） - 这是与可卡因渴望认知控制有关的区域。重要的是，MPFC中遗漏提示激活的神经元的选择性破坏阻止了OCI的后续表达。因此，1）MPFC中遗漏提示引起的神经激活介导OCI。由于神经激活是局部兴奋性神经传递的产物，因此OCI可能受到2）MPFC中的遗漏提示激活的兴奋性神经传递，以及3）3）遗漏提示提示激活的兴奋性兴奋性传入的神经神经化的MPFC-已知的大脑底物可为诱导Neural Actication in MpFC诱导MPFC。考虑到上述情况，该项目将检验以下总体假设：可卡因寻求的OCI受到遗漏提示激活的兴奋性神经传递的控制，并且在MPFC中驱动明显的神经激活的传入者。提出三个目的是建立内侧前额叶皮质1）神经表型，2）神经化学信号和3）神经记录，负责可卡因遗漏提示复发抑制。总体而言，预期的结果将建立主动抑制（而不是促进可卡因复发）的大脑机制，因此提出了阻止复发的新见解。