Acoustic startle reduction in cocaine dependence

声学惊吓可减少可卡因依赖

• 批准号: 7379982
• 负责人: Erica J Duncan
• 金额: $ 34.87万
• 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/7379982
• 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

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.

长期服用可卡因会导致大脑功能发生变化，这种变化在急性发作后仍持续很长时间 退出阶段。声学惊吓反应 (ASR) 是一种对声音的反射性反应。 突然的声刺激。 ASR 由一个简单的 3 突触皮层下回路介导；它被调制在 部分由与可卡因给药相关的大脑区域和神经递质决定。我们的初步研究和 随后的复制揭示了可卡因依赖受试者在短暂的睡眠后 ASR 显着降低 禁欲期。对于这种强烈异常发生的确切时间进程知之甚少 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，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，并不早于他们对可卡因成瘾的时间 脆弱性因素。我们的初步调查结果表明，可卡因依赖者的一级亲属 与健康对照组相比，受试者的惊吓程度也有所减少。大鼠中低 ASR 的发现 人类在可卡因清除期间和家庭成员的低 ASR 表明可能同时存在一种特征和 我们报告的令人震惊的减少的国家部分。 我们提出了一个包含临床和临床前组成部分的转化项目，这将推进我们的研究 了解可卡因相关惊吓减少的临床意义和潜在病理生理学。 该提案的中心目标是剖析这一发现的发展和 人类（具体目标 1 和 2）和大鼠在可卡因戒断早期和晚期阶段的持续性 （具体目标5）；以确定惊吓减少及其在以后的潜在正常化 戒断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）； 并检查惊吓减少是否至少部分是发展的脆弱性特征 可卡因依赖（具体目标 4）。后一个目标将通过测试人类的兄弟姐妹来实现 可卡因依赖受试者，以及通过评估高可卡因与低可卡因依赖性受试者对可卡因自我给药的脆弱性。 低惊老鼠。 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。意义 这项工作的重点在于 ASR 减少作为可靠、易于重复的生物方法的潜力 测量可卡因引起的大脑变化可能会增强结果预测，以便制定量身定制的治疗方案 考虑到可用资源的限制，可能会针对那些最容易复发的患者 用于药物滥用治疗。