Cognitive Processes for Pharmacotherapy Development and Treatment Outcome Incoca

描述(由申请人提供)：应聘者的长期职业目标是成为药物疗法开发领域的一名独立研究员，以增强药物滥用人群的认知能力。建议的多学科指导计划将通过在a)药物治疗开发试验的进行和评估，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，以及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，提供结构化的监督和指导技术，从而帮助向独立研究过渡。可卡因依赖是美国最常见、最可预防的医疗保健问题之一。最重要的是，与可卡因依赖相关的认知障碍可能是药物治疗干预的独特靶点，因为它们可能反映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。虽然许多研究试图阐明与可卡因依赖相关的认知困难，但相对较少的研究集中于确定哪些认知过程代表了药物治疗开发的有效靶点，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α2肾上腺素能激动剂，它能中枢抑制去甲肾上腺素(NE)相关的应激系统，并已被证明能减少应激诱导的可卡因渴求和应激诱导的可卡因依赖患者的负面情绪。由于压力、奖赏和认知大脑系统的重叠，减少压力系统唤醒和可卡因强化的药物也可能影响特定的认知过程，如抑制控制。因此，候选人建议设计一系列神经认知任务，这些任务将衡量抑制性控制(和相关的认知因素)，将对金刚烷的增强效果敏感，并将成为治疗结果的良好预测指标。拟议的导师研究科学家发展奖(MRSDA)项目将在目前资助的一项为期9周(3周住院患者和6周门诊患者)的双盲安慰剂对照治疗试验中增加神经认知电池，评估瓜那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治疗三周后对神经认知电池的测试。此外，随后六周的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。特定药物改善认知过程的可能性可能支持目标导向行为，包括冲动、自我监控决策，这可能是降低复发风险的关键，从而对个人福利和社会卫生保健成本产生广泛影响。通过K01 MRSDA提供的有组织的培训机会，候选人将能够制定一项富有成效的研究计划，重点是识别药物滥用障碍药物治疗开发的显著认知过程。 公共卫生相关性：迫切需要的不仅是为可卡因依赖开发新的药物疗法，而且还需要确定衡量治疗效果的容易量化的目标。选择性认知过程中的困难可能反映了与可卡因强化有关的大脑系统变化，以及与物质滥用行为变化相关的目标导向行为的基础。这些因素包括冲动、自律和决策。因此，选择性认知过程的减少，如抑制控制，可能是药物治疗干预的有效靶点，也是可卡因治疗结果的重要中介。我们认为，由于应激、奖赏和认知大脑系统的重叠，金刚烷已被证明可以减少应激诱导的交感兴奋和应激诱导的可卡因渴求，因此它还可能改善某些认知过程。因此，当前提案的目标是选择一系列神经认知测试，这些测试将对盐酸胍法辛治疗对住院可卡因依赖患者的增强效果敏感，也可能是门诊治疗期间可卡因复发和复发因素的良好预测指标。由于认知功能低下可能是导致成瘾的许多行为过程的基础，用药物缓解这些困难可能有助于减少复发的脆弱性，从而减少许多使人虚弱的可卡因依赖症状。因此，对初级学者进行培训，使其精通认知药物疗法开发研究，对于改善易受伤害和吸毒成瘾人群的健康和福利至关重要。

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. PUBLIC HEALTH RELEVANCE: There is a pressing need not only to develop new pharmacotherapies for cocaine dependence, but also to identify easily quantifiable targets for measuring treatment efficacy. Difficulties in selective cognitive processes may reflect brain system changes involved in cocaine reinforcement as well as underlie goal-oriented behaviors associated with changes in substance abuse behavior. These include impulsivity, self-regulation and decision making. As such, decrements in selective cognitive processes, such as inhibitory control, may represent efficacious targets for pharmacotherapy intervention as well as important mediators of cocaine treatment outcome. As guanfacine has been shown to decrease stress-induced sympathetic arousal and stress-induced cocaine craving, we suggest that it may also improve certain cognitive processes, due to an overlap in stress, reward and cognitive brain systems. The objectives of the current proposal are therefore to select a battery of neurocognitive tests that will be sensitive to the enhancing effects of guanfacine hydrochloride treatment in cocaine dependent inpatients, and which may also be good predictors of cocaine relapse and relapse factors during outpatient treatment. As poor cognitive function may underlie so many behavioral processes sub-serving addiction, ameliorating these difficulties with pharmacological agents may serve to reduce relapse vulnerability and thus many of the debilitating symptoms of cocaine dependence. Training junior scholars to proficiency with regard to the conduct of cognitive pharmacotherapy development research is therefore critical to improving the health and welfare of vulnerable and addicted populations.