Reinstatement of cocaine seeking by social defeat

描述（由申请人提供）：可卡因滥用在美国是一个主要的公共卫生问题，但没有fda批准的药物疗法存在。可卡因滥用和依赖障碍的一个突出特征是频繁发生复发。由于已知心理困扰和负面情绪影响会诱发成瘾个体的药物渴望和促进复发，因此了解压力和成瘾过程之间的关系可能有助于确定有效的药物和/或预防复发的行为策略。使用恢复程序在实验动物中经常模拟药物使用的复发。在这个范例中，动物被训练成通过操作性反应（例如杠杆按压）自我管理滥用药物。一旦自我给药行为稳定，反应可以通过抑制药物可用性和/或与药物相关的环境刺激而消失。一旦熄灭，反应可以通过将动物暴露于各种刺激（包括压力）来“恢复”。然而，在动物中最常用的恢复可卡因寻求行为的压力源是物理和药理学压力源，与在人类中引起渴望和促进复发的心理压力源相比，这些压力源缺乏表面有效性。社会失败压力发生在野生和实验室老鼠身上，可以通过将一只“入侵者”老鼠放入一只“常驻”领土老鼠的家笼子中产生。“居民”将迅速威胁并最终击败“入侵者”。重要的是，闯入者所经历的心理压力已被描述为药物滥用者在复发前所经历的心理社会压力类型的有效模型。然而，社会失败压力是否会恢复动物的可卡因寻求行为尚未被调查。因此，本研究计划旨在开发和描述暴露于行为学上有效的社会心理压力源（社会失败）后大鼠应激诱导恢复的新模型。老鼠将被训练自我使用可卡因，随后会被消灭。第一组实验将确定暴露在急性或反复的社会失败压力下是否会恢复可卡因寻求行为，如果是这样，其潜在机制是否与先前描述的物理和药理学压力源不同。此外，众所周知，社会失败压力会增强可卡因的许多与滥用相关的影响，一组单独的实验将检验近期有社会失败暴露史的大鼠是否会增强可卡因启动恢复。总的来说，这些研究的结果将是第一次描述临床前模型

DESCRIPTION (provided by applicant): Cocaine abuse is a major public health concern in the United States, yet no FDA-approved pharmacotherapies exist. A prominent feature of cocaine abuse and dependence disorders is the frequent occurrence of relapse episodes. Because psychological distress and negative emotional affect are known to induce drug craving and promote relapse in addicted individuals, an understanding of the relationship between stress and addictive processes may help identify effective medications and/or behavioral strategies for relapse prevention. Relapse to drug use is frequently modeled in experimental animals using the reinstatement procedure. In this paradigm, animals are trained to self-administer drugs of abuse via operant responding (e.g. lever-press). Once self-administration behavior is stable, responding can be extinguished by withholding drug availability and/or drug-associated environmental stimuli. Once extinguished, responding can be "reinstated" by exposing the animal to various stimuli, including stress. However, the most commonly-used stressors to reinstate cocaine- seeking behavior in animals are physical and pharmacological stressors which lack face validity as compared to psychological stressors that induce craving and promote relapse in humans. Social defeat stress occurs in both wild and laboratory rats and can be engendered by placing an "intruder" rat into the home cage of a "resident" territorial rat. The "resident" will quickly threaten and ultimately defeat the "intruder". Importantly, the psychologicl stress experienced by the intruder has been described as a valid model of the types of psychosocial stress that drug abusers experience prior to a relapse episode. However, whether social defeat stress reinstates cocaine-seeking behavior in animals has not been investigated. This research proposal therefore aims to develop and characterize a novel model of stress-induced reinstatement in rats following exposure to the ethologically-valid psychosocial stressor, social defeat. Rats will be trained to self-administer cocaine and responding will subsequently be extinguished. The first set of experiments will determine whether exposure to acute or repeated social defeat stress reinstates cocaine- seeking behavior, and if so, whether the underlying mechanisms are different from those described previously for physical and pharmacological stressors. Furthermore, as it is known that social defeat stress enhances many of the abuse-related effects of cocaine, a separate set of experiments will examine whether cocaine-primed reinstatement is potentiated in rats with a recent history of social defeat exposure. Overall, the results of these studies would be the first to describe a preclinical model of drug relapse using a rodent psychosocial stressor that closely models the types of stressors that have been found to induce craving and promote relapse in human substance abusers. With such a model available, it may be possible to subsequently identify novel pharmacotherapeutic and/or behavioral strategies to mitigate the effects of psychosocial stress and facilitate relapse prevention in individuals with substance abuse disorders.