Acoustic startle reduction in cocaine dependence

长期服用可卡因会导致脑功能的改变，这种改变在急性可卡因中毒后很长一段时间内仍会持续 停药阶段。声学惊厥反应(ASR)是一种对 突然的声学刺激。ASR是由一个简单的3-突触皮质下回路介导的；它在 部分原因是与可卡因注射相关的脑区和神经递质。我们的初步研究和 随后的复制显示可卡因依赖者的ASR在短暂的 禁欲时期。关于这种强烈异常的确切时间进程，我们知之甚少。 发展起来。我们团队和其他人使用啮齿动物模型的研究也表明，在 反复服用可卡因，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并没有，至少部分地，在他们对可卡因上瘾之前 脆弱性因素。我们的初步发现表明可卡因依赖的一级亲属 与健康对照组相比，受试者的惊吓程度也有所降低。大鼠低ASR和低ASR的表现 吸食可卡因期间的人类和家庭成员的低ASR表明，可能有一种特征和 我们已经报道了令人震惊的减少的州部分。 我们提出了一个包含临床和临床前组件的翻译项目，该项目将推进我们的 了解可卡因相关惊厥减少的临床意义和潜在的病理生理学。 这项提案的中心目标是剖析这一发现关于其发展和 可卡因戒断早期和后期在人类(特定目标1和2)和大鼠中的持久性 (具体目标5)；确定惊吓的减少及其在以后可能的正常化 戒酒是可卡因依赖受试者临床病程的预测因子(特定目标3)； 并研究惊吓减少是否至少在一定程度上是导致 可卡因依赖(具体目标4)。后一个目标将在人类身上通过测试兄弟姐妹来实现 在可卡因依赖的受试者中，并通过评估高剂量组和高剂量组大鼠对可卡因自身给药的易感性。 低级惊吓的老鼠。 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。它的意义 这项工作的关键在于ASR的降低有可能成为一种可靠的、易于重复的生物学 测量可卡因引起的大脑变化，可能会增强结果预测，以便量身定做的治疗 可能针对那些最容易复发的患者，考虑到可用资源的限制 接受药物滥用治疗。

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 for available for substance abuse treatment.