Cognitive Processes for Pharmacotherapy Development and Treatment Outcome Incoca

描述（由申请人提供）：候选人的长期职业目标是成为药物滥用人群认知增强药物治疗发展领域的独立研究人员。提出了一个多学科指导计划，通过提供结构化的监督和教学技术，帮助他们过渡到独立研究：A)药物治疗开发试验的实施和评估；b)对认知和成瘾的神经生物学和药理学基础的理论和实践理解；c)与多时间点和结果的药物治疗试验相关的数据分析技术。可卡因依赖是美国最常见和可预防的健康问题之一。最重要的是，与可卡因依赖相关的认知困难可能是药物治疗干预的独特目标，因为它们可能反映了与复发相关的大脑变化，以及与治疗结果相关的目标导向行为的基础。虽然许多研究试图阐明与可卡因依赖相关的认知困难，但相对较少的研究侧重于确定哪些认知过程是药物治疗发展的有效目标，哪些过程是可卡因治疗结果的良好预测因素。盐酸胍法辛是一种α 2肾上腺素能激动剂，可中枢抑制去甲肾上腺素（NE）相关的应激系统，并可减少可卡因依赖患者应激诱导的可卡因渴求和应激诱导的负性情绪。由于压力、奖励和认知脑系统的重叠，减少应激系统唤醒和可卡因强化的药理学制剂也可能影响特定的认知过程，如抑制控制。因此，候选人建议设计一组神经认知任务来测量抑制控制（以及相关的认知因素），将对胍法辛的增强作用敏感，并将是治疗结果的良好预测因子。拟议的指导研究科学家发展奖（MRSDA）项目将在目前资助的9周（3周住院和6周门诊）双盲，安慰剂对照治疗试验中增加神经认知电池，评估胍法辛剂量的药物治疗效果。这将为候选人提供基础设施，以测试一组90名可卡因依赖者在基线和住院三周的胍法辛治疗后的神经认知电池。此外，随后的六周门诊试验将允许候选人评估复发和复发因素作为认知改善的功能。特定药理学制剂改善认知过程的潜力，这可能是支持目标导向行为的基础，包括冲动，自我监控决策，可能对降低复发风险至关重要，因此对个人福利和社会医疗保健成本具有广泛的影响。通过K01 MRSDA提供的结构化培训机会，候选人将能够开发一个富有成效的研究项目，专注于识别药物滥用障碍药物治疗发展的显著认知过程。

DESCRIPTION (provided by applicant): The candidate's long term career goal is to become an independent researcher within the field of pharmacotherapy development for cognitive enhancement in substance-abusing populations. A multidisciplinary mentoring program is proposed that will help assist the transition to independent research by providing structured supervision and didactic techniques in a) the conduct and assessment of pharmacotherapy development trials, b) a theoretical and practical understanding of the neurobiological and pharmacological basis of cognition and addiction, and c) data analytical techniques relevant to pharmacotherapy trials with multiple time-points and outcomes. Cocaine dependence is one of the most common and preventable health care problems in the US. Most importantly, cognitive difficulties associated with cocaine dependence may represent unique targets for pharmacotherapy intervention as they may reflect relapse-related brain changes as well as underlie goal-oriented behaviors associated with treatment outcome. While many studies have tried to elucidate the difficulties in cognition associated with cocaine dependence, relatively few studies have focused on identifying which cognitive processes represent effective targets for pharmacotherapy development and which processes are good predictors of cocaine treatment outcome. Guanfacine hydrochloride is an alpha2 adrenergic agonist, which centrally inhibits norepinephrine (NE)-related stress systems and has been shown to reduce stress-induced cocaine craving and stress-induced negative mood in cocaine dependent patients. Pharmacological agents that reduce stress system arousal and cocaine reinforcement may also impact specific cognitive processes, such as inhibitory control, due to an overlap in stress, reward and cognitive brain systems. The candidate therefore proposes to devise a battery of neurocognitive tasks that will measure inhibitory control (and associated cognitive factors), will be sensitive to the enhancing effects of guanfacine and will be good predictors of treatment outcome. The proposed Mentored Research Scientist Development Award (MRSDA) project will add a neurocognitive battery onto a currently funded nine week (3 weeks inpatient and 6 weeks outpatient) double blind, placebo controlled treatment trial assessing the pharmacotherapeutic effects of guanfacine dose. This will provide the candidate with the infrastructure to test a group of ninety cocaine dependent individuals on a neurocognitive battery both at baseline and following three weeks of inpatient guanfacine treatment. In addition, a subsequent six week outpatient trial will allow the candidate to assess relapse and relapse factors as a function of cognitive improvement. The potential for specific pharmacological agents to ameliorate cognitive processes that may underpin goal-directed behaviors including impulsivity, self-monitoring decision-making may be critical to reducing risk of relapse and thus have a wide ranging impact on individual welfare and societal health care costs. Through the structured training opportunity afforded by the K01 MRSDA the candidate will be able to develop a productive program of research focused on identifying salient cognitive processes for pharmacotherapy development in substance abusing disorders.