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

描述（由申请人提供）：可卡因成瘾是一种慢性复发性障碍，其特征是强迫性可卡因使用。大量的努力致力于揭示神经行为因素负责促进渴望和药物寻求。尽管作出了这些努力，但预防可卡因复吸的有效干预措施尚未确立。因此，另一种研究策略可能是有益的。为此，开发了“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信号可卡因遗漏（不可用）的线索的复发抑制潜力。初步结果表明，一个新的发现，尽管历史上的强迫性可卡因摄入，遗漏线索抑制可卡因寻求引发的所有主要模式的复发促进（药物线索，压力和可卡因启动）以及可卡因摄入。额外的结果表明，遗漏线索诱导Fos（神经激活的标志物）在一个离散的神经元亚群定位在内侧前额叶皮层（mPFC）-一个区域涉及的认知控制可卡因的渴望。重要的是，选择性破坏mPFC中的遗漏线索激活神经元阻断了随后的OCIS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可能由2）mPFC中的遗漏线索激活的兴奋性神经传递以及3）mPFC的遗漏线索激活的兴奋性传入神经支配控制-已知提供驱动以诱导mPFC中的神经激活的脑底物。考虑到上述情况，本项目将测试总体假设，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传入驱动不同的神经激活mPFC控制的。提出了三个目标，以建立内侧前额叶皮层1）神经表型，2）神经化学信号和3）负责可卡因遗漏线索的复发抑制的神经回路。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吸的大脑机制，从而为阻断复吸提供新的见解。

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.