Reinstatement of cocaine seeking by social defeat

由于社会失败而恢复可卡因寻求

基本信息

批准号：
8662737
负责人：
DAVID WEINSHENKER
金额：
$ 7.8万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8662737
关键词：
Abstinence Acute Affect Affective Animal Experimentation Animals Attenuated Behavior Behavior Therapy Behavioral Brain Cocaine Cocaine Abuse Cocaine Dependence Communities Disease Distress Dose Drug usage Emotional Event Exhibits Exposure to Extinction (Psychology)FDA approved Face Foundations Frequencies Goals Home environment Human Individual Laboratory Rat Lead Mediating Modeling Neurobiology Pathway interactions Pharmaceutical Preparations Pharmacotherapy Pre-Clinical Model Procedures Process Psychological Stress Psychosocial Stress Public Health Rattus Recording of previous events Relapse Research Research Personnel Research Project Grants Research Proposals Rodent Schedule Self Administration Self-Administered Stimulus Stress Substance abuse problem Sucrose System Testing Training United States Yohimbine addiction cocaine use craving disorder later incidence prevention drug abuser drug craving drug of abuse drug relapse drug seeking behavior experience footshock induced neurobiological mechanism novel prevent psychologic psychological distress psychological stressor psychosocial public health relevance research study social stressor substance abuser theories treatment program

项目摘要

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.

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，但尚无 FDA 批准的药物疗法。可卡因滥用和依赖性障碍的一个突出特点是频繁发生复发。由于已知心理困扰和负面情绪影响会诱发成瘾者对药物的渴望并促进成瘾者复吸，因此了解压力与成瘾过程之间的关系可能有助于确定预防复吸的有效药物和/或行为策略。经常使用恢复程序在实验动物中模拟吸毒复发。在这种范例中，动物被训练通过操作反应（例如杠杆按压）自行施用滥用药物。一旦自我给药行为稳定，可以通过停止提供药物和/或与药物相关的环境刺激来消除反应。一旦反应消失，可以通过将动物暴露于各种刺激（包括压力）来“恢复”反应。然而，在动物中恢复可卡因寻求行为的最常用压力源是身体和药理学压力源，与诱发人类渴望和促进复吸的心理压力源相比，这些压力源缺乏表面有效性。野生和实验室老鼠都会出现社交失败压力，并且可以通过将“入侵者”老鼠放入“居民”领地老鼠的笼子中来产生。 “居民”会迅速威胁并最终击败“入侵者”。重要的是，入侵者经历的心理压力已被描述为药物滥用者在复发之前经历的心理社会压力类型的有效模型。然而，社交失败压力是否会恢复动物的可卡因寻求行为尚未得到研究。因此，本研究提案旨在开发和表征一种在暴露于行为学上有效的心理社会压力源（社交失败）后的压力诱导恢复的新模型。老鼠将被训练自我注射可卡因，随后反应就会消失。第一组实验将确定暴露于急性或反复的社交失败压力是否会恢复可卡因寻求行为，如果是的话，其潜在机制是否与之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与滥用相关的影响，一组单独的实验将检查可卡因引发的恢复是否会在最近有社交失败暴露史的老鼠中得到加强。总的来说，这些研究的结果将是第一个描述临床前模型的研究结果使用啮齿类动物心理社会压力源来研究药物复发，该压力源与已发现的会引起人类药物滥用者渴望并促进药物滥用的压力源类型密切相关。有了这样的模型，随后就有可能确定新的药物治疗和/或行为策略，以减轻心理社会压力的影响并促进药物滥用障碍患者复发的预防。