Neural Substrates of Anxiety in Acute Opiate Dependence

描述（由申请人提供）：难以治疗海洛因等药物成瘾者的原因之一是戒断与强烈的负面情绪有关。如果我们理解了戒断引起的负面情绪的神经生物学，这可能会为药物滥用的新的和更成功的预防/干预治疗提供一条途径。这项建议将审查阿片类药物依赖的神经基板使用“急性”依赖的范例，其中退出评估后，一个单一的阿片类药物暴露。急性依赖范式特别适合于研究药物依赖初期阶段所涉及的神经适应机制。惊吓反射的增强已经被广泛用于焦虑和恐惧的研究，它将作为一种客观、可靠和分级的衡量戒断引起的负面情绪的方法。拟开展的研究将探讨脑内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，在急性吗啡戒断期间，将评价由下丘脑释放CRF介导的下丘脑-垂体-肾上腺（HPA）轴的激活。第二，将确定阻断HPA轴激活对急性阿片依赖的影响。第三，CRF受体激活在急性依赖中的作用将通过在戒断发作前颅内微量输注选择性CRF受体拮抗剂来研究。这些研究将为进一步表征急性阿片类药物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。

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.