Role of Endogenous Opiate Systems in Cocaine Relapse after Long-Term Abstinence

内源性阿片系统在长期戒断后可卡因复发中的作用

• 批准号: 8605866
• 负责人: David W Self
• 金额: $ 34.27万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605866
• 关键词: Abstinence; Agonist; Antibodies; Behavior; Behavior Control; Behavioral; Biochemical; Biochemical Markers; Biological; Biological Phenomena; Cell Nucleus; Cells; Chronic; Cocaine; Cocaine Dependence; Data; Disease; Drug Addiction; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Extinction (Psychology); Fiber Optics; Gel; Goals; Health; Human; Hypothalamic structure; In Situ Hybridization; Infusion procedures; Measures; Mediating; Mental disorders; Morphine; Mus; Neurons; Nucleus Accumbens; Opioid Receptor; Peptides; Phase; Phosphorylation; Play; Pro-Opiomelanocortin; Regulation; Relapse; Research; Rhodopsin; Rodent Model; Role; Self Administration; Signal Transduction; Societies; Structure of nucleus infundibularis hypothalami; Synapses; System; Testing; Therapeutic Intervention; Time; Up-Regulation; Viral Vector; Western Blotting; Withdrawal; adeno-associated viral vector; base; beta-Endorphin; connective tissue-activating peptide; economic cost; endogenous opioids; in vivo; nerve supply; neuroadaptation; neurobiological mechanism; novel; optogenetics; promoter; recombinase; research study; response; severe mental illness; social

DESCRIPTION (provided by applicant): Drug addiction is a serious and prolific mental illness involving persistent relapse despite sincere efforts to abstain. This research studies the neurobiological mechanisms that increase the propensity for relapse after prolonged abstinence to determine novel targets for potential therapeutic intervention to promote abstinence. Previous studies suggest that mu opiate receptor stimulation in the nucleus accumbens (NAc) does not play a role in cocaine-seeking behavior using rodent models of cocaine relapse. However, we found that NAc infusions of the endogenous opiate beta-endorphinwill trigger cocaine seeking primarily via activation of mu opiate receptors (MOR1) in the NAc. Importantly, we found that MOR1 expression in the NAc progressively increases from early to late cocaine withdrawal, coinciding with time-dependent increases (incubation) in cocaine-seeking behavior. Moreover, our preliminary data suggest that increases in MOR1 expression in the NAc are paralleled by increased expression of the beta-endorphinprecursor proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (Arc). The goal of the proposed research is to study the functional contribution of neuroadaptations in these endogenous opiate systems to the increased propensity for relapse in long-term cocaine withdrawal. Studies in Aim I will determine the ability of MOR1 stimulation in the NAc to trigger relapse behavior after early and late withdrawal from chronic cocaine self-administration. Intra-NAc infusions of beta-endorphinand the MOR1 agonist DAMGO will be tested for their ability to increase relapse behavior in both extinction and reinstatement phases of experimentation. Similar intra-NAc infusions of DAMGO will be used to assess MOR1 signaling in vivo as a biochemical parallel to behavioral experiments. Studies in Aim II will use in situ hybridization to measure POMC expression in the Arc, and In Gel Western Blot of beta-endorphinlevels in the Arc and NAc, after both early and late withdrawal times. The contribution of increased POMC expression and beta-endorphin synthesis to the propensity for relapse will be studied by neutralizing endogenous beta-endorphinrelease in the NAc with anti-beta-endorphin and the MOR1 antagonist CTAP in extinction/reinstatement tests. Stressful situations activate POMC neurons in the Arc, and trigger cocaine-seeking behavior, but the role of POMC neurons in relapse behavior has not been studied. Studies in Aim III will investigate the effects of selective activation of POMC Arc neurons on cocaine seeking in early and late withdrawal using an optogenetic approach combining inducible viral vector-mediated channel-rhodopsin-2 expression in mice expressing Cre recombinase under POMC promoter control. The role of beta-endorphinrelease in the NAc in relapse induced by activation of POMC neurons will be assessed with intra-NAc infusions of anti-beta-endorphin. Together, these studies will determine the role of persistent neuroadaptations in endogenous mu opiate receptor systems in the increased propensity for cocaine relapse in prolonged abstinence.

描述（由申请人提供）：吸毒成瘾是一种严重且多发的精神疾病，尽管真诚地努力戒毒，但仍会持续复发。这项研究研究了长期禁欲后增加复发倾向的神经生物学机制，以确定促进禁欲的潜在治疗干预的新目标。先前的研究表明，使用可卡因复发的啮齿动物模型，伏隔核（NAc）中的μ阿片受体刺激在可卡因寻求行为中不起作用。然而，我们发现，内源性阿片β-内啡肽的NAc输注将主要通过激活NAc中的μ阿片受体（MOR1）来触发可卡因寻找。重要的是，我们发现 NAc 中的 MOR1 表达从可卡因戒断早期到晚期逐渐增加，与可卡因寻求行为的时间依赖性增加（潜伏期）一致。此外，我们的初步数据表明，NAc 中 MOR1 表达的增加与下丘脑弓状核 (Arc) 中 β-内啡肽前体阿片黑皮素原 (POMC) 表达的增加是平行的。拟议研究的目的是研究这些内源性阿片系统中的神经适应对长期可卡因戒断复发倾向增加的功能贡献。 Aim I 的研究将确定 NAc 中 MOR1 刺激在早期和晚期戒断慢性可卡因自我给药后触发复发行为的能力。 NAc 内注射 β-内啡肽和 MOR1 激动剂 DAMGO 将在实验的消退和恢复阶段测试其增加复发行为的能力。类似的 DAMGO 内 NAc 输注将用于评估体内 MOR1 信号传导，作为与行为实验平行的生化实验。 Aim II 的研究将使用原位杂交来测量 Arc 中的 POMC 表达，以及在早期和晚期撤药时间后，使用凝胶蛋白质印迹法测量 Arc 和 NAc 中的 β-内啡肽水平。 POMC 表达和 β-内啡肽合成增加对复发倾向的贡献将通过在消退/恢复测试中用抗 β-内啡肽和 MOR1 拮抗剂 CTAP 中和 NAc 中的内源性 β-内啡肽释放来研究。压力情况会激活弧区的 POMC 神经元，并引发寻求可卡因的行为，但 POMC 神经元在复吸行为中的作用尚未被研究。 Aim III 的研究将使用光遗传学方法，结合在 POMC 启动子控制下表达 Cre 重组酶的小鼠中诱导病毒载体介导的通道视紫红质 2 表达，研究选择性激活 POMC Arc 神经元对早期和晚期戒断中可卡因寻求的影响。 NAc 中 β-内啡肽释放在 POMC 神经元激活诱导的复发中的作用将通过 NAc 内输注抗 β-内啡肽进行评估。总之，这些研究将确定内源性μ阿片受体系统中持续神经适应在长期戒断可卡因复发倾向增加中的作用。