Target Validation Core Rats

描述(由申请人提供)：本申请提出了INIA-WEST联盟的核心组成部分，任务是确定治疗酒精中毒的目标药物。将根据从INIA-WEST项目中获得的信息确定代理人。这些药物将接受检查，以确定它们是否会使用老鼠已有的行为方法，系统地改变反映酒精中毒各方面的行为，包括酗酒、消极情绪和全神贯注预期。试验以有序的方式进行，对于继续或停止使用某一试剂的研究，有明确的决策点。通过在累进比率时间表下维持可操作的酒精自我给药和有希望的结果，以及随后的位置调节和2瓶偏爱程序，检查了代理人改变指示狂欢中毒的行为的能力。消极情绪的缓解是通过测量戒断迹象以及焦虑和抑郁样行为，通过高架加迷宫和强迫游泳测试来评估的。全神贯注-预期(“渴望”)是通过药物/线索诱导的已熄灭操作物反应的恢复、条件性方法和手势跟踪来评估的。鉴于预防复发在酒精中毒治疗中的重要性，这组“渴望”研究是拨款的重点，也是使用大鼠的一个原因，因为这些程序在小鼠身上更难建立。此外，由于过量饮酒会导致认知缺陷，这可能会干扰心理治疗(通常与药物治疗相结合)，我们还将评估靶标制剂是否使用标准的学习和记忆任务(例如，恐惧条件作用、物体识别、延迟交替)改变认知功能。研究将在长期接触酒精蒸气的大鼠身上进行。该项目与罗伯茨和贝尔项目密切互动，以确认或扩大调查结果，从而增强对所取得成果的信心。最后，我们将与其他项目和核心合作，利用分子遗传学和神经药理学方法，确认靶向药物改变慢性酒精效应的神经生物学效应。 公共卫生相关性：该研究计划的目标是为INIA-WEST联盟建立一个行为测试核心，旨在测试潜在的酒精中毒药物治疗剂。这个核心的主要焦点是进行反映“渴望”的测试，尽管酒精中毒的其他方面(醉酒，负面影响)将被解决，并将结果与贝尔和罗伯茨的核心进行比较。

DESCRIPTION (provided by applicant): This application proposes a core integral to the INIA-West Consortium tasked to identify target medications to treat alcoholism. Agents will be identified based on information obtained from projects within INIA-West. The agents will be examined to determine if they alter behaviors reflective of the various aspects of alcoholism including binge-intoxication, negative affect, and preoccupation-anticipation in a systematic manner using established behavioral methods with rats. Tests are conducted in an orderly manner with clearly defined decision points for continuation or cessation of studies with an agent. An agent's ability to alter behaviors indicative of binge-intoxication is examined using maintenance of operant self-administration of alcohol under progressive ratio schedules and promising results followed by place conditioning and 2-bottle preference procedures. Alleviation of negative affect is assessed by measuring withdrawal signs and anxiety- and depressive-like behaviors with elevated plus maze and forced swim tests. Preoccupation-anticipation ("craving") is assessed with drug/cue-induced reinstatement of extinguished operant responding, conditioned approach, and sign-tracking. This set of "craving" studies is a focal point of the grant given the importance of relapse prevention in alcoholism treatment and a reason rats are used as these procedures are more difficult to establish with mice. Further, because excessive alcohol can cause cognitive deficits that would likely interfere with psychological treatments (which are often combined with pharmacological treatments), we will also assess whether target agents alter cognitive function using standard learning and memory tasks (e.g., fear conditioning, object recognition, delayed alternation). Studies will be conducted in rats that have been chronically exposed to alcohol vapors. This project interacts closely with the Roberts and Bell projects to confirm or extend findings allowing greater confidence in results obtained. Finally, in collaboration with other projects and cores and using molecular genetic and neuropharmacological approaches, we will confirm the neurobiological effects of the target agents to alter chronic alcohol effects. PUBLIC HEALTH RELEVANCE: The goal of this research program is to establish a behavioral testing core for the INIA-West Consortium aimed at testing potential pharmacotherapeutic agents for alcoholism. The main focus of this core is to conduct tests reflective of "craving" although other aspects of alcoholism (intoxication, negative affect) will be addressed and results compared to those of the Bell and Roberts cores.