Acoustic startle reduction in cocaine dependence

描述（由申请人提供）：长期服用可卡因可导致急性戒断期后长期持续的脑功能改变。声惊反应（ASR）是对突发声刺激的反射性反应。ASR是由一个简单的3突触皮层下回路介导的；它在一定程度上是由与可卡因服用有关的大脑区域和神经递质调节的。我们最初的研究和随后的重复研究表明，在短暂的戒断后，可卡因依赖者的ASR显著降低。人们对这种强健异常发生的确切时间过程知之甚少。我们小组和其他人使用啮齿动物模型的工作也表明，反复服用可卡因后ASR减少，这与我们的临床发现一致。然而，我们不能确定，这些受试者的惊吓减少，至少在一定程度上，不是在他们的可卡因成瘾作为一个脆弱性因素之前。我们的初步研究结果表明，与健康对照相比，可卡因依赖者的一级亲属也减少了惊吓。大鼠和人类在可卡因洗脱期间的低ASR以及家庭成员的低ASR的发现表明，我们报道的惊吓减少可能有特征和状态两方面的因素。我们提出了一个包含临床和临床前成分的转化项目，这将促进我们对可卡因相关惊吓减少的临床意义和潜在病理生理学的理解。本提案的中心目标是剖析这一发现在人类（具体目标1和2）和大鼠（具体目标5）可卡因戒断的早期和后期阶段的发展和持久性；确定在后来的戒断期间惊吓减少及其潜在的正常化是否可以预测人类可卡因依赖受试者的临床病程（特定目标3）；并检查惊吓减少是否，至少在一定程度上，是可卡因依赖发展的易感性特征（具体目标4）。后一项研究将在人类中进行，通过测试可卡因依赖对象的兄弟姐妹，并在大鼠中进行，通过评估高惊吓与低惊吓大鼠对可卡因自我给药的脆弱性。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的减少有可能作为一种可靠的、容易重复的可卡因引起的大脑变化的生物学测量，可以增强结果预测，以便针对那些最容易复发的患者进行量身定制的治疗，考虑到药物滥用治疗的可用资源有限。

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.