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: 9235211
• 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/9235211
• 关键词: AMPA Receptors; Acetylcholine; Acute; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Automobile Driving; Behavioral Paradigm; Biological Assay; Brain; Choline O-Acetyltransferase; Chronic; Cues; Disease; Dopamine; Drug Addiction; Drug Controls; Fluoro-Gold; Glutamate Decarboxylase; Glutamates; Grant; 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; public health relevance; 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饮酒为特征的慢性复发性疾病。人们致力于揭示促进复发的神经行为因素。尽管做出了这些努力，但预防酒精复吸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。在此前提下，开发了“遗漏线索诱导抑制（OCIS）范式”来研究表明酒精遗漏（无法获得）的线索的复发抑制潜力。初步结果表明，遗漏线索会抑制所有主要的复发促进模式（酒精线索、压力和酒精本身）引发的寻酒行为。值得注意的是，遗漏线索会抑制正在经历急性或长期戒断（与高复发风险相关的情况）的酒精依赖受试者的酒精寻求。其他初步结果表明，OCIS 受以下因素控制：1）内侧前额皮质 (mPFC) 中遗漏线索激活神经元的离散亚群，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 可能由 2）mPFC 中遗漏提示激活的兴奋性传递以及 3）mPFC 遗漏提示激活的兴奋性传入神经支配控制 - 已知提供驱动力诱导 mPFC 中的神经激活。考虑到上述情况，该项目将测试总体假设，即酒精寻求的 OCIS 是由遗漏线索激活的兴奋性神经传递和驱动 mPFC 中不同神经激活的传入神经控制的。提出了三个目标。目标 1 将重点关注 mPFC 中遗漏提示激活的神经元。目标 2 将重点关注 mPFC 中遗漏线索激活的兴奋性神经传递。目标 3 将重点关注遗漏提示激活的 mPFC 兴奋性传入输入。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，从而为阻止复发提供新的见解。