Reinstatement of cocaine seeking by social defeat

描述（由申请人提供）：可卡因滥用是美国的一个主要公共卫生问题，但没有FDA批准的药物治疗。可卡因滥用和依赖性障碍的一个突出特点是经常复发。由于心理困扰和负面情绪影响是已知的，以诱导药物渴望和促进复发成瘾的个人，压力和成瘾过程之间的关系的理解可能有助于确定有效的药物和/或行为策略，复发预防。使用复吸程序经常在实验动物中模拟药物使用的复发。在这种模式中，动物被训练通过操作性反应（例如，按压）自我施用滥用药物。一旦自我给药行为稳定，可以通过抑制药物可用性和/或药物相关的环境刺激来消除反应。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，在动物中恢复可卡因寻求行为的最常用的应激源是物理和药理应激源，其与在人类中诱导渴望和促进复发的心理应激源相比缺乏表面有效性。 社会失败压力发生在野生和实验室的大鼠，可以通过将“入侵者”大鼠放入“居民”领土大鼠的家笼中产生。“居民”会迅速威胁并最终击败“入侵者”。重要的是，入侵者所经历的心理压力被描述为药物滥用者在复发发作之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还没有研究。因此，本研究建议的目的是开发和表征一种新的模型的压力诱导的恢复大鼠暴露后的行为学有效的心理社会压力，社会失败。将训练大鼠自我施用可卡因，随后将消除反应。第一组实验将确定暴露于急性或重复的社会失败压力是否会恢复可卡因寻求行为，如果是这样，潜在的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，社交失败压力会增强可卡因的许多滥用相关效应，因此将进行一组单独的实验，以检查最近有社交失败暴露史的大鼠是否会增强可卡因引发的恢复。 总的来说，这些研究的结果将是第一个描述临床前模型的结果。 使用啮齿类动物的心理社会应激源，密切模拟已被发现在人类物质滥用者中诱导渴望和促进复发的应激源类型。有了这样一个模型，它可能是可能的，随后确定新的药物和/或行为策略，以减轻心理社会压力的影响，并促进预防复发的个人与物质滥用障碍。

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.