Acoustic startle reduction in cocaine dependence

描述（由申请人提供）：长期可卡因给药导致脑功能变化，在急性戒断期后持续很长时间。声惊吓反应（acoustic startle response，ASR）是一种对突发声刺激的反射性反应。ASR由简单的3-突触皮层下回路介导;它部分地由与可卡因给药相关的脑区和神经递质调节。我们的初步研究和随后的重复研究揭示了可卡因依赖受试者在短暂戒断后ASR的显著减少。很少有人知道确切的时间过程中，这种强大的异常发展。我们小组和其他人使用啮齿动物模型的工作也表明，在反复服用可卡因后，ASR降低，这与我们的临床发现一致。然而，我们不能确定这些受试者的惊人减少至少在一定程度上没有早于他们的可卡因成瘾作为脆弱性因素。我们的初步研究结果表明，可卡因依赖受试者的一级亲属与健康对照组相比也减少了惊吓。在可卡因洗脱期间，大鼠和人类的低ASR以及家庭成员的低ASR的发现表明，我们报告的惊吓减少可能既有特征也有状态成分。我们提出了一个翻译项目，临床和临床前的组成部分，将促进我们的临床意义和可卡因相关的惊吓减少的基础病理生理学的理解。本提案的中心目标是剖析这一发现，即在人类可卡因戒断的早期和后期阶段，（具体目标1和2）和大鼠（具体目的5）;确定在后来戒断期间惊吓减少及其潜在正常化是否是可卡因依赖人类受试者临床病程的预测因子（具体目标3）;并审查惊吓减少是否至少部分是可卡因依赖发展的脆弱性特征（具体目标4）。后一个目标将通过测试可卡因依赖受试者的兄弟姐妹在人类中进行，并通过评估高与低惊吓大鼠对可卡因自我给药的脆弱性在大鼠中进行。与公共卫生的相关性：可卡因依赖是一个巨大的公共卫生问题。这项工作的意义在于，ASR降低可能作为可卡因诱导的大脑变化的可靠，易于重复的生物学测量，这可能会增强结果预测，以便针对那些最容易复发的患者进行量身定制的治疗，因为药物滥用治疗的资源有限。

DESCRIPTION (provided by applicant): Chronic cocaine administration leads to changes in brain function that persist long after the acute withdrawal phase. The acoustic startle response (ASR) is a well characterized reflexive response to a sudden acoustic stimulus. The ASR is mediated by a simple 3-synapse subcortical circuit; it is modulated in part by brain areas and neurotransmitters associated with cocaine administration. Our initial study and subsequent replication reveals a profound diminution of the ASR in cocaine-dependent subjects after a brief period of abstinence. Little is known about the exact time course during which this robust abnormality develops. Work using rodent models by our group and others also indicates a reduction in the ASR after recurrent cocaine administration that is consistent with our clinical finding. However, we cannot be certain that startle reductions in these subjects did not, at least in part, predate their cocaine addiction as a vulnerability factor. Our preliminary findings indicate that first degree relatives of cocaine-dependent subjects also have reduced startle compared to healthy controls. The findings of low ASR in rats and humans during cocaine washout and low ASR in family members suggests there may be both a trait and state component of the startle reductions we have reported. We propose a translational project with both clinical and preclinical components that will advance our understanding of the clinical significance and underlying pathophysiology of cocaine-related startle reduction. The central objectives of this proposal are to dissect this finding with regard to its development and persistence in early and later phases of cocaine abstinence in humans (Specific Aims 1 and 2) and in rats (Specific Aims 5); to ascertain whether startle reduction and its potential normalization during later abstinence is a predictor of clinical course in human subjects with cocaine dependence (Specific Aim 3); and to examine whether startle reduction is, at least in part, a vulnerability trait for the development of cocaine dependence (Specific Aim 4). This latter Aim will be carried out in humans by testing siblings of cocaine-dependent subjects, and in rats by evaluating vulnerability to cocaine self-administration in high- vs. low-startling rats. Relevance to Public Health: Cocaine dependence is an enormous public health problem. The significance of this work lies in the potential for the ASR reduction to serve as a reliable, easily repeatable biological measure of cocaine-induced brain changes that may enhance outcome prediction so that tailored treatments may be directed at those patients most vulnerable to relapse, given the restriction of resources available for substance abuse treatment.