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

基本信息

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
项目类别：
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

项目摘要

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）：可卡因成瘾是一种慢性复发性疾病，其特征是强迫性使用可卡因。人们致力于揭示促进渴望和药物寻求的神经行为因素。尽管做出了这些努力，但预防可卡因复吸的有效干预措施尚未建立。因此，另一种研究策略可能会被证明是有益的。在此前提下，开发了一种“遗漏线索诱导抑制（OCIS）范式”，以研究具有强迫性可卡因摄入史的大鼠中可卡因遗漏（不可利用）信号的线索抑制复发的潜力。初步结果表明，一项新颖的发现表明，尽管有强迫性可卡因摄入的历史，遗漏线索抑制了所有主要的复发促进模式（药物线索、压力和可卡因启动）以及可卡因摄入所引发的可卡因寻求。其他结果表明，遗漏线索会在位于内侧前额叶皮层 (mPFC) 内的离散神经元亚群中诱导 Fos（神经激活标记），该区域与可卡因渴望的认知控制有关。重要的是，选择性破坏 mPFC 中遗漏提示激活的神经元会阻止 OCIS 的后续表达。因此，1) 遗漏线索诱导的 mPFC 神经激活介导 OCIS。因为神经激活是局部兴奋性神经传递的产物，所以 OCIS 可能是由 2）mPFC 中遗漏提示激活的兴奋性神经传递以及 3）mPFC 遗漏提示激活的兴奋性传入神经支配控制的——已知这些脑基质可提供驱动诱导 mPFC 中的神经激活。考虑到上述情况，该项目将测试一个总体假设，即可卡因寻求的 OCIS 是由遗漏线索激活的兴奋性神经传递和驱动 mPFC 中不同神经激活的传入神经控制的。提出了建立内侧前额皮质的三个目标：1）神经表型，2）神经化学信号和3）负责通过可卡因遗漏线索抑制复发的神经回路。总的来说，预期的结果将建立积极抑制而不是促进可卡因复发的大脑机制，从而为阻止复发提供新的见解。