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

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性疾病。大量的研究致力于揭示促进渴望和药物寻求的神经行为因素。尽管作出了这样的努力，但预防可卡因复发的有效干预措施尚未确立。因此，另一种研究策略可能被证明是有益的。在此前提下，研究人员建立了一种“遗漏线索诱导抑制（OCIS）范式”，以研究有强迫性可卡因摄入史的大鼠中暗示可卡因遗漏（不可用）的线索对复发的抑制潜力。初步结果表明，尽管有强迫性可卡因摄入的历史，但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）以及可卡因摄入引发的可卡因寻求。另外的结果表明，遗漏线索在位于内侧前额叶皮层（mPFC）的一个离散的神经元亚群中诱导Fos（一种神经激活的标记），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中遗漏线索激活的神经元阻断了OCIS的后续表达。因此，1)遗漏线索诱导的mPFC神经激活介导了OCIS。由于神经激活是局部兴奋性神经传递的产物，OCIS可能受以下因素控制：2)遗漏线索激活的mPFC兴奋性神经传递，以及3)遗漏线索激活的mPFC -脑底物的兴奋性传入神经支配，这些底物提供了诱导mPFC神经激活的驱动。综上所述，本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mPFC中驱动不同神经激活的传入事件控制的。本文提出了建立内侧前额叶皮层的三个目的：1)神经表型；2)神经化学信号；3)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，因此为阻止复发提供了新的见解。

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.