Acoustic startle reduction in cocaine dependence

声学惊吓可减少可卡因依赖

• 批准号: 7236696
• 负责人: Erica J Duncan
• 金额: $ 33.08万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7236696
• 关键词: Abstinence; Abstinence Syndrome; Acoustics; Acute; Address; Area; Biological; Brain; Brain Part; Characteristics; Chromosome Pairing; Chronic; Clinical; Cocaine; Cocaine Dependence; Complement; Data; Deltastab; Development; Disruption; Dopamine; Dopamine D1 Receptor; Dose; Family member; First Degree Relative; Functional disorder; Funding; Future; Genetic; Heritability; Hour; Human; Intoxication; Literature; Measures; Mediating; Modeling; Neurotransmitters; Outcome; Patients; Phase; Public Health; Rattus; Recording of previous events; Recurrence; Relapse; Relative (related person); Reporting; Research Personnel; Resource Allocation; Resources; Rest; Risk; Rodent; Rodent Model; Role playing therapy; Self Administration; Self-Administered; Severities; Siblings; Stimulus; Substance abuse problem; Synapses; System; Testing; Time; Twin Multiple Birth; Week; Withdrawal; Work; base; clinically significant; cohort; day; design; human study; human subject; pre-clinical; prevent; programs; receptor function; research study; response; trait

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.

描述(由申请人提供)：长期服用可卡因会导致大脑功能的变化，这种变化在急性戒断阶段后很长一段时间内仍然存在。声学惊吓反应(ASR)是一种对突发性声刺激的反射性反应。ASR是由一个简单的3-突触皮质下回路介导的；它部分受到与可卡因注射相关的脑区和神经递质的调节。我们最初的研究和随后的复制显示，在短暂的戒毒期后，可卡因依赖受试者的ASR显著减少。对于这种强烈异常发展的确切时间进程，我们知之甚少。我们团队和其他人使用啮齿动物模型的研究也表明，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易感因素。我们的初步发现表明，与健康对照组相比，可卡因依赖者的一级亲属也减少了惊吓。在吸食可卡因的过程中，大鼠和人类的ASR降低，家庭成员的ASR降低，这一发现表明，我们所报道的惊吓减少可能既有特征也有状态成分。我们提出了一个包含临床和临床前成分的翻译项目，这将促进我们对可卡因相关惊厥减少的临床意义和潜在病理生理学的理解。这项建议的中心目标是分析这一发现在可卡因戒断的早期和后期在人类(具体目标1和2)和大鼠(具体目标5)中的发展和持久性；确定惊厥减少及其在戒除后期的潜在正常化是否是可卡因依赖受试者临床病程的预测指标(具体目标3)；以及审查惊吓减少是否至少部分是可卡因依赖形成的易损性特征(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身上实现，并在大鼠身上通过评估高惊吓大鼠和低惊吓大鼠对可卡因自我注射的脆弱性来实现。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的减少有可能成为一种可靠的、易于重复的可卡因诱导的大脑变化的生物学衡量标准，这可能会增强结果预测，从而在可用于药物滥用治疗的资源有限的情况下，针对那些最容易复发的患者进行量身定制的治疗。