Target Validation Core Rats

描述（由申请人提供）：本申请提出了nia - west联盟的核心组成部分，其任务是确定治疗酒精中毒的目标药物。代理商将根据从nia - west项目中获得的信息确定。研究人员将对这些药物进行检查，以确定它们是否能以一种系统的方式改变反映酒精中毒各个方面的行为，包括酗酒、负面影响和专注预期。试验以有序的方式进行，并明确定义继续或停止使用某种药物进行研究的决策点。通过在递进比例计划下维持可操作性的自我酒精管理，以及随后的场所条件反射和2瓶偏好程序，检查代理人改变指示性狂欢中毒行为的能力。负面影响的缓解是通过测量戒断症状和焦虑和抑郁样行为来评估的，这些行为包括升高的迷宫和强迫游泳测试。关注-期待（“渴望”）是通过药物/线索诱导的已消失的操作性反应的恢复、条件反射和信号跟踪来评估的。考虑到酗酒治疗中预防复发的重要性，这组“渴望”研究是拨款的焦点，也是使用大鼠的原因，因为这些程序更难在小鼠身上建立。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），我们还将评估目标药物是否会通过标准的学习和记忆任务（例如，恐惧条件反射、物体识别、延迟交替）改变认知功能。研究将在长期暴露于酒精蒸气的大鼠身上进行。该项目与Roberts和Bell项目密切互动，以确认或扩展发现，从而对所获得的结果更有信心。最后，与其他项目和核心合作，并使用分子遗传学和神经药理学方法，我们将确认目标药物改变慢性酒精效应的神经生物学效应。

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.