Acoustic startle reduction in cocaine dependence

描述(申请人提供)：这项提案的概念框架是基于这样一种观点，即可卡因依赖会导致脑多巴胺(DA)系统的长期变化，从而使长期吸毒者在戒断后长期处于低多巴胺状态。声学惊厥反应(ASR)是一种特征明确的皮质下反射，受伏隔核多巴胺活动的调节，伏隔核是药物渴求的重要区域。在短暂戒毒后，可卡因依赖者的ASR显著减少，这与低多巴胺状态一致。临床前研究还表明，反复服用可卡因后ASR减少。人们对这种异常发展的确切时间进程和机制知之甚少。这一提议将检验一种假说，即慢性可卡因依赖会导致功能性低多巴胺的持续状态，这种状态反映在惊吓幅度的显著降低上。这项建议的中心目标是(1)描述这一发现在可卡因戒断初期和后期的发展和持久性，(2)确定ASR减少的严重程度和ASR在长期戒断期间未能正常化是否是临床病程的预测指标，(3)确定ASR减少是可卡因依赖特有的还是可推广到对其他刺激物的依赖，以及(4)研究可卡因依赖受试者的ASR，以确定惊吓幅度降低是否是可卡因依赖的家族(通过推断是遗传)易感性的标志。该项目的一个长期目标是了解长期接触可卡因与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改进可卡因依赖患者的亚型。实现后一个目标可以增强结果预测，因此，考虑到可用于治疗这种破坏性成瘾的资源的严格限制，量身定制的治疗可能针对最容易复发的患者。

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.