Acoustic startle reduction in cocaine dependence

声学惊吓可减少可卡因依赖

• 批准号: 7275232
• 负责人: Erica J Duncan
• 金额: $ 4.42万
• 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/7275232
• 关键词: Acoustic; startle; reduction; cocaine; dependence

DESCRIPTION (provided by applicant): The conceptual framework of this proposal is based on the contention that cocaine dependence leads to long term changes in the brain dopamine (DA) system that leave the chronic user in a prolonged state of hypodopaminergia after abstinence. The acoustic startle response (ASR) is a well-characterized subcortical reflex that is modulated by DA activity in the nucleus accumbens, a region important for drug craving. There is a profound diminution of the ASR in cocaine-dependent subjects after brief abstinence that is consistent with a hypodopaminergic state. Preclinical work also indicates a reduction in the ASR after recurrent cocaine administration. Little is known about the exact time course and mechanism by which this abnormality develops. This proposal would test a hypothesis that chronic cocaine dependence causes a persistent state of functional hypodopaminergia that is reflected in profound startle amplitude reduction. The central objectives of this proposal are (1) to characterize this finding with regard to its development and persistence in initial and later phases of cocaine abstinence, (2) to determine whether severity of ASR reduction and failure of the ASR to normalize during prolonged abstinence is a predictor of clinical course, (3) to determine whether ASR reduction is specific to cocaine dependence or generalizable to dependence on other stimulants, and (4) to study ASR in well siblings of cocaine-dependent subjects to determine whether reduced startle amplitude is a marker of a familial (and by inference genetic) vulnerability to develop cocaine dependence. A long-range goal of this project is to understand the course and clinical significance of the association of prolonged cocaine exposure with marked reductions in ASR amplitude, and to refine the subtyping of cocaine-dependent patients based on the severity of this abnormality. Achieving the latter goal could enhance outcome prediction so that tailored treatments may be directed at patients most vulnerable to relapse, given the severe restriction of resources available for treatment of this destructive addiction.

描述（由申请人提供）：本提案的概念框架基于以下论点：可卡因依赖导致大脑多巴胺（DA）系统的长期变化，使长期使用者在戒断后长期处于多巴胺能减退状态。声惊吓反应（ASR）是一种典型的皮质下反射，它受到多巴胺（DA）在延髓核（一个对药物渴求很重要的区域）活动的调节。可卡因依赖受试者短暂戒断后ASR显著降低，这与多巴胺能减退状态一致。临床前研究还表明，复发性可卡因给药后ASR降低。关于这种异常发展的确切时间进程和机制知之甚少。这一提议将检验一个假设，即慢性可卡因依赖导致持续状态的功能性多巴胺能减退，反映在深刻的惊吓幅度减少。该提案的中心目标是（1）描述这一发现在可卡因戒断初期和后期的发展和持续性，（2）确定在长期戒断期间ASR降低的严重程度和ASR未能正常化是否是临床病程的预测因子，（3）确定ASR降低是可卡因依赖特有的还是可推广到对其他兴奋剂的依赖，（4）研究可卡因依赖受试者健康同胞的ASR，以确定惊吓幅度降低是否是家族性（并通过推断遗传）易患可卡因依赖的标志。该项目的长期目标是了解长期可卡因暴露与ASR幅度显著降低之间的关系的过程和临床意义，并根据这种异常的严重程度来细化可卡因依赖患者的亚型。实现后一个目标可以提高结果预测，使量身定制的治疗可以针对最容易复发的患者，鉴于严重限制资源可用于治疗这种破坏性的成瘾。