Neural Substrates of Anxiety in Acute Opiate Dependence

描述（由申请人提供）：难以治疗海洛因等毒品成瘾者的原因之一是，戒断与强烈的负面情绪有关。如果我们了解戒断诱导的负面情绪的神经生物学，这可能为药物滥用提供新的和更成功的预防/干预治疗途径。本提案将使用“急性”依赖范式来研究阿片类药物依赖的神经基质，其中在单次阿片类药物暴露后评估戒断。急性依赖范式特别适合于研究药物依赖初期的神经适应机制。惊反射的增强已经广泛应用于焦虑和恐惧的研究，它将作为一种客观、可靠和分级的方法来衡量戒断诱发的负面影响。拟议的研究将检查神经肽促肾上腺皮质激素释放因子（CRF）受体在急性阿片类药物依赖中的作用。首先，下丘脑-垂体-肾上腺（HPA）轴的激活，是由下丘脑释放CRF介导的，将在急性吗啡戒断期间进行评估。第二，阻断下丘脑轴激活对急性阿片依赖的影响将被确定。第三，通过在停药前颅内微量输注选择性CRF受体拮抗剂，研究CRF受体激活在急性依赖中的作用。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，朝着开发治疗药物依赖的新治疗方法的长期目标努力。

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.