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

描述(申请人提供)：可卡因成瘾是一种慢性复发性疾病，特征是强迫性使用可卡因。人们一直致力于揭示导致渴求和寻求毒品的神经行为因素。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建立。因此，另一种研究策略可能会被证明是有益的。在这一前提下，一个“遗漏线索诱导抑制(OCIS)范式”被开发出来，用来研究在有强迫性吸食可卡因历史的大鼠中，发出可卡因遗漏(不可用)信号的线索对复发的抑制潜力。初步结果表明，一项新的发现表明，尽管有强制吸食可卡因的历史，但遗漏线索抑制了由所有主要的复发促进模式(药物线索、压力和可卡因激发)以及可卡因摄入引发的可卡因寻求。其他结果表明，遗漏线索在内侧前额叶皮质(MPFC)内的一个离散神经元亚群中诱导Fos(神经激活的标志)-这是一个与可卡因渴望的认知控制有关的区域。重要的是，选择性地阻断mPFC中遗漏线索激活的神经元阻止了随后的OCIS的表达。因此，1)遗漏线索诱导的mPFC神经激活参与了OCIS的调节。由于神经激活是局部兴奋性神经传递的产物，OCIS可能由2)遗漏线索激活的mPFC兴奋性神经传递以及3)遗漏线索激活的兴奋性传入神经支配mPFC-脑底物提供了诱导mPFC神经激活的动力。考虑到上述情况，本项目将检验最重要的假设，即寻找可卡因的OCI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控制的。提出了三个目标，以建立内侧前额叶皮质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。总而言之，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。

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.