Relapse-suppressing brain mechanisms in alcoholism: role of the mPFC

描述(申请人提供)：酒精依赖是一种慢性复发性障碍，以强迫性饮酒为特征。人们一直致力于揭示促进复发的神经行为因素。尽管做出了这样的努力，但防止酗酒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”被用来研究暗示酒精遗漏(不可用)的线索对复发的抑制潜力。初步结果表明，遗漏线索抑制了由所有促进复发的主要模式引发的酒精寻求：酒精线索、压力和酒精本身。值得注意的是，在经历急性或长期戒断的酒精依赖受试者中，遗漏线索抑制了酒精寻求--这种情况与复发的高风险有关。另外的初步结果表明，OCIS由1)内侧前额叶皮质(MPFC)中一个离散的遗漏线索激活神经元亚群控制--该区域与成瘾者对药物渴望的认知控制有关。鉴于神经激活是局部兴奋性神经传递的产物，OCIS可能受2)遗漏线索激活的mPFC兴奋性传递以及3)遗漏线索激活的兴奋传入到mPFC-脑底物的控制，已知的mPFC-脑底物提供了诱导神经激活的动力。有鉴于此，本项目将验证酒精寻求的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这一总体假设。提出了三个目标。目标1将重点放在mPFC中遗漏线索激活的神经元。目的2将重点放在遗漏线索激活的兴奋性神经传递在mPFC。目标3将重点放在遗漏线索激活的兴奋性传入到mPFC。总而言之，预期的结果将建立积极抑制--而不是促进--酒精复发的大脑机制，从而为阻止复发提供新的见解。

DESCRIPTION (provided by applicant): Alcohol dependence is a chronic relapsing disorder characterized by compulsive alcohol use. Significant effort has been dedicated to reveal neurobehavioral factors responsible for promoting relapse. Despite such effort, effective interventions to prevent alcohol 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 alcohol omission (unavailability). Preliminary results indicate that omission cues suppress alcohol seeking triggered by all major modes of relapse-promotion: alcohol cues, stress and alcohol itself. Remarkably, omission cues suppress alcohol seeking in alcohol dependent subjections undergoing acute or protracted withdrawal - conditions linked to high risk of relapse. Additional preliminary results indicate that OCIS is controlled by 1) a discrete subpopulation of omission cue-activated neurons in the medial prefrontal cortex (mPFC) - a region implicated in cognitive control of drug craving in addicts. Given that the neural activation is a product of loca excitatory neurotransmission, OCIS is likely controlled by 2) omission cue-activated excitatory transmission 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 alcohol seeking is controlled by omission cue-activated excitatory neurotransmission and afferents driving distinct neural activation in mPFC. Three Aims are proposed. Aim 1 will focus on omission cue-activated neurons in mPFC. Aim 2 will focus on omission cue-activated excitatory neurotransmission in mPFC. Aim 3 will focus on omission cue-activated excitatory afferent inputs to mPFC. Collectively, the expected results will establish brain mechanisms that actively suppress - rather than promote - alcohol relapse, and therefore present new insights for blocking relapse.