Acoustic startle reduction in cocaine dependence

声学惊吓可减少可卡因依赖

• 批准号: 7586104
• 负责人: Erica J Duncan
• 金额: $ 27.76万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586104
• 关键词: Abstinence; Abstinence Syndrome; Acoustics; Acute; Address; Area; Biological; Brain; Brain Part; Characteristics; Chronic; Clinical; Cocaine; Cocaine Dependence; Complement; Data; Deltastab; Development; 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; Play; Public Health; Rattus; Recording of previous events; Recurrence; Relapse; Relative (related person); Reporting; Research Personnel; Resource Allocation; Resources; Rest; Risk; Rodent; Rodent Model; Role; Self Administration; Self-Administered; Severities; Siblings; Stimulus; Substance abuse problem; System; Testing; Time; Twin Multiple Birth; Withdrawal; Work; base; clinically significant; cocaine exposure; cocaine use; cohort; design; human subject; pre-clinical; prevent; programs; receptor function; research study; response; trait; treatment response

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的变化，这种变化在急性可卡因中毒后很长时间内仍会持续。 戒断阶段声惊吓反应（ASR）是一种很好的反射性反应， 突然的声音刺激ASR由一个简单的3-突触皮层下回路介导;它在 一部分是通过与可卡因给药相关的大脑区域和神经递质。我们的初步研究和 随后的复制显示，可卡因依赖受试者在短暂的 禁欲期。关于这种强烈异常的确切时间过程知之甚少 发展起来的我们小组和其他人使用啮齿动物模型的工作也表明， 反复服用可卡因与我们的临床发现一致。但是，我们不能确定 这些受试者的惊人减少并没有，至少部分地，早于他们的可卡因成瘾， 脆弱性因素我们的初步发现表明可卡因依赖者的一级亲属 与健康对照相比，受试者也具有减少的惊吓。大鼠低ASR的发现， 人类在可卡因洗脱期间和家庭成员中的低ASR表明， 我们报告的惊吓减少的状态组成部分。 我们提出了一个具有临床和临床前组成部分的转化项目， 了解可卡因相关惊吓减少的临床意义和基础病理生理学。 本提案的中心目标是从其发展的角度剖析这一结论， 人（具体目标1和2）和大鼠可卡因戒断早期和晚期的持久性 （具体目标5）;确定惊吓减少及其在以后期间的潜在正常化 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是，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。 可卡因依赖的受试者，并在大鼠中通过评估可卡因自我管理的脆弱性，在高vs. 低惊鼠 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 这项工作的潜力在于减少ASR作为一种可靠的，易于重复的生物学方法， 可卡因引起的大脑变化的测量，可能会增强结果预测， 鉴于现有资源有限， 进行药物滥用治疗

项目成果

Lack of relationship between acoustic startle and cognitive variables in schizophrenia and control subjects.

• DOI: 10.1016/j.psychres.2011.02.011
• 发表时间: 2011-05-30
• 期刊: PSYCHIATRY RESEARCH
• 影响因子: 11.3
• 作者: Hasenkamp, Wendy;Kelley, Mary;Egan, Glenn;Green, Amanda;Wilcox, Lisette;Boshoven, William;Lewison, Barbara;Duncan, Erica
• 通讯作者: Duncan, Erica

Altered engagement of attention and default networks during target detection in schizophrenia.

• DOI: 10.1016/j.schres.2010.08.041
• 发表时间: 2011-02
• 期刊: SCHIZOPHRENIA RESEARCH
• 影响因子: 4.5
• 作者: Hasenkamp, Wendy;James, G. Andrew;Boshoven, William;Duncan, Erica
• 通讯作者: Duncan, Erica

Heritability of acoustic startle magnitude, prepulse inhibition, and startle latency in schizophrenia and control families.

• DOI: 10.1016/j.psychres.2009.11.012
• 发表时间: 2010-07-30
• 期刊: PSYCHIATRY RESEARCH
• 影响因子: 11.3
• 作者: Hasenkamp, Wendy;Epstein, Michael P.;Green, Amanda;Wilcox, Lisette;Boshoven, William;Lewison, Barbara;Duncan, Erica
• 通讯作者: Duncan, Erica