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治疗开发领域的独立研究人员，以提高物质滥用人群的认知能力。提出了一个多学科的指导计划，这将有助于通过提供结构化的监督和教学技术，以协助过渡到独立的研究a）药物治疗开发试验的进行和评估，B）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）与多个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，但相对较少的研究专注于确定哪些认知过程代表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子。盐酸胍法辛是一种α 2肾上腺素能激动剂，其中枢抑制去甲肾上腺素（NE）相关的应激系统，并已显示可减少可卡因依赖患者中应激诱导的可卡因渴望和应激诱导的负面情绪。减少应激系统唤醒和可卡因强化的药理学药物也可能影响特定的认知过程，例如抑制控制，这是由于应激、奖励和认知脑系统的重叠。因此，候选人建议设计一系列神经认知任务，这些任务将测量抑制控制（和相关的认知因素），对胍法辛的增强作用敏感，并且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为期9周（3周住院和6周门诊）的双盲安慰剂对照治疗试验中增加神经认知电池，以评估胍法辛剂量的药效。这将为候选人提供基础设施，以在基线和三周住院胍法辛治疗后对一组90名可卡因依赖者进行神经认知成套测试。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函数。特定药理学药物改善认知过程的潜力可能是降低复发风险的关键，从而对个人福利和社会医疗保健成本产生广泛影响，这些认知过程可能支持目标导向行为，包括冲动性、自我监测决策。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计划，重点是确定药物滥用障碍药物治疗开发的突出认知过程。 公共卫生相关性：迫切需要的不仅是开发治疗可卡因依赖的新药物疗法，而且还需要确定易于量化的目标，以衡量治疗效果。选择性认知过程的困难可能反映了可卡因强化所涉及的大脑系统变化，以及与物质滥用行为变化相关的目标导向行为的基础。这些包括冲动，自我调节和决策。因此，选择性认知过程（如抑制控制）的减少可能代表药物治疗干预的有效靶点以及可卡因治疗结果的重要介导物。由于胍法辛已被证明可以减少压力引起的交感神经兴奋和压力引起的可卡因渴望，我们认为它也可以改善某些认知过程，由于压力，奖励和认知大脑系统的重叠。因此，本提案的目的是选择一组神经认知测试，这些测试对盐酸胍法辛治疗可卡因依赖住院患者的增强作用敏感，并且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因子。由于认知功能不佳可能是许多行为过程的基础，因此使用药物改善这些困难可能有助于减少复发的脆弱性，从而减少可卡因依赖的许多衰弱症状。因此，培训初级学者熟练进行认知药物疗法开发研究，对改善弱势和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.