Neural Substrates of Anxiety in Acute Opiate Dependence

急性阿片依赖中焦虑的神经基础

• 批准号: 7098429
• 负责人: JONATHAN GEWIRTZ
• 金额: $ 7.2万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7098429
• 关键词: adrenalectomy; behavioral /social science research tag; corticosterone; corticotropin releasing factor; drug addiction; drug withdrawal; emotions; hypothalamic pituitary adrenal axis; laboratory rat; microinjections; morphine; motivation; neuropeptide receptor; neuropharmacology; opiate alkaloid; protein structure function; receptor expression; startle reaction

DESCRIPTION (provided by applicant): One of the reasons that it is difficult to treat individuals who are addicted to drugs like heroin is that withdrawal is associated with intense negative emotions. If we understood the neurobiology of withdrawal induced negative emotionality, this might provide an avenue for novel and more successful prevention/intervention treatments for drug abuse. This proposal will examine the neural substrates of opiate dependence using an "acute" dependence paradigm, in which withdrawal is assessed following a single opiate exposure. Acute dependence paradigms are especially well suited for studying the neuroadaptive mechanisms involved in the incipient stages of drug dependence. Potentiation of the startle reflex, which is already widely used in studies of anxiety and fear, will serve as an objective, reliable, and graded measure of withdrawal-induced negative affect. The proposed studies will examine the role of receptors of the neuropeptide corticotropin releasing factor (CRF) in the brain in acute opiate dependence. First, activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is mediated by release of CRF from the hypothalamus, will be evaluated during withdrawal from acute morphine. Second, the effects of blockade of HPA axis activation on acute opiate dependence will be determined. Third, the role of CRF receptor activation in acute dependence will be investigated, through intracranial microinfusion of a selective CRF receptor antagonist prior to the onset of withdrawal. These studies will lay the groundwork for further characterization of the neural substrates of acute opiate dependence, working towards the long-term goal of developing novel therapeutic approaches for treating drug dependence.

描述（由申请人提供）：海洛因等药物成瘾者难以治疗的原因之一是戒断与强烈的负面情绪相关。如果我们了解戒断引起的负面情绪的神经生物学，这可能为药物滥用的新颖且更成功的预防/干预治疗提供一条途径。该提案将使用“急性”依赖范式检查阿片依赖的神经基质，其中在单次阿片暴露后评估戒断情况。急性依赖范式特别适合研究药物依赖初期阶段涉及的神经适应性机制。惊吓反射的增强已经广泛应用于焦虑和恐惧的研究中，它将作为戒断引起的负面情绪的客观、可靠和分级的衡量标准。拟议的研究将检查大脑中神经肽促肾上腺皮质激素释放因子（CRF）受体在急性阿片依赖中的作用。首先，将在急性吗啡戒断期间评估下丘脑-垂体-肾上腺 (HPA) 轴的激活，该轴是由下丘脑释放 CRF 介导的。其次，将确定阻断 HPA 轴激活对急性阿片依赖的影响。第三，将通过在戒断开始前颅内微量输注选择性 CRF 受体拮抗剂来研究 CRF 受体激活在急性依赖性中的作用。这些研究将为进一步表征急性阿片依赖的神经基质奠定基础，致力于开发治​​疗药物依赖的新治疗方法的长期目标。