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

酗酒中抑制复发的大脑机制：mPFC 的作用

• 批准号: 9031014
• 负责人: Nobuyoshi Suto
• 金额: $ 42.64万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-10 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031014
• 关键词: AMPA Receptors; Acetylcholine; Acute; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Automobile Driving; Behavioral Paradigm; Biological Assay; Brain; Chemicals; Choline O-Acetyltransferase; Chronic; Cues; Disease; Dopamine; Drug Addiction; Fluoro-Gold; Glutamate Decarboxylase; Glutamates; Grant; Health; High Pressure Liquid Chromatography; Immunohistochemistry; Intake; Interneurons; Intervention; Label; Link; Medial; Mediating; Medical; Methods; Microdialysis; Molecular; Monitor; N-Methyl-D-Aspartate Receptors; Nature; Neurons; Norepinephrine; Output; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Population; Prefrontal Cortex; Rattus; Relapse; Research; Role; Serotonin; Signal Transduction; Stress; Techniques; Testing; Tracer; Withdrawal; alcohol availability; alcohol craving; alcohol cue; alcohol relapse; alcohol seeking behavior; base; calmodulin-dependent protein kinase II; cholinergic; cognitive control; drug craving; effective intervention; extracellular; gamma-Aminobutyric Acid; high risk; improved; insight; nerve supply; neurobehavioral; neurochemistry; neurotransmission; novel; prevent; psychosocial; relapse risk; relating to nervous system; transmission process

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.

描述（由申请人提供）：酒精依赖是一种以强迫性酒精使用为特征的慢性复发性障碍。大量的研究致力于揭示促进复发的神经行为因素。尽管作出了这样的努力，但预防酒精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，研究人员开发了一种“遗漏线索诱导抑制（OCIS）范式”，以研究提示酒精遗漏（不可得性）的线索对复发的抑制潜力。初步结果表明，遗漏线索抑制了所有主要促进复发模式（酒精线索、压力和酒精本身）引发的酒精寻求。值得注意的是，在急性或长期戒断的酒精依赖者中，遗漏线索抑制了对酒精的寻求——这种情况与复发的高风险有关。额外的初步结果表明，OCIS是由1)内侧前额叶皮层（mPFC）中一个离散的遗漏线索激活神经元亚群控制的，该区域与成瘾者对药物渴望的认知控制有关。考虑到神经激活是局部兴奋性神经传递的产物，OCIS可能是由2)遗漏线索激活的mPFC兴奋性传递和3)遗漏线索激活的mPFC -脑底物的兴奋性传入神经支配控制的，这些脑底物提供了诱导mPFC神经激活的驱动。综上所述，本项目将测试一个总体假设，即酒精寻求的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。提出了三个目标。目的1将重点关注mPFC中的遗漏线索激活神经元。目的2将集中于遗漏线索激活的mPFC兴奋性神经传递。目的3将关注遗漏线索激活的兴奋性传入输入到mPFC。总的来说，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，因此为阻止复发提供了新的见解。