Functional neuroanatomy underlying psychosocial stress-induced cocaine seeking

 描述(申请人提供)：可卡因滥用和依赖障碍的一个突出特征是经常发生复发，通常是由心理痛苦和/或负面情绪造成的。药物复吸通常是使用恢复程序在实验动物中模拟的。在这个范例中，动物首先被训练通过操纵性反应(例如杠杆按压)自我管理滥用药物，然后这种反应通过不注射药物来“熄灭”。一旦熄灭，反应可以通过将动物暴露在包括压力在内的各种刺激下来“恢复”。然而，通常用于恢复动物寻找可卡因行为的应激源本质上是物理或药理上的，而心理社会应激源更接近于通常在人类中引发渴望和引发复发的应激类型。这一点非常令人担忧，因为许多研究表明，调节对心理社会压力反应的大脑回路可能不同于调节对其他形式的压力反应的回路。为了解决药物滥用研究中的这一空白，我开发了一种新的恢复程序，在该程序中，大鼠的可卡因寻找行为是由心理社会压力而不是身体或药物压力引发的。这一范式中使用的心理社会应激源是同质性的社会失败，这种失败可以通过将一只“入侵者”老鼠放入一只更大的“常驻”领地老鼠的家笼子中而产生。“居民”会迅速威胁并最终诱使“入侵者”屈服。重要的是，入侵者经历的痛苦被认为与吸毒者在复发之前经历的心理社会压力类型密切相关。我假设，与其他应激源相比，心理社会应激诱导的可卡因寻求是由不同的神经回路介导的，可能包括大脑中高度保守的“防御”系统的组成部分。在目标1(K99阶段)中，我将使用c-fos免疫组织化学技术绘制在心理社会或身体压力下寻求可卡因所产生的大脑激活模式，以识别在心理社会压力诱导的恢复过程中选择性激活的区域。在AIMS 2和3(R00阶段)中，我将使用我在K99阶段获得的培训，应用化学遗传方法(设计师受体的位点特异性表达，DREADD)来确定防御回路的组件是否与观察到的药物寻找反应存在因果联系。这些研究的结果可能会对我们理解压力和成瘾过程之间的相互作用产生深远的影响，并将为未来旨在进一步表征心理社会应激诱导的药物寻求行为的神经生物学特征的工作奠定基础。这些研究的最终目标是确定新的行为和/或药物治疗策略，以防止应激诱导的药物复发。

 DESCRIPTION (provided by applicant): A prominent feature of cocaine abuse and dependence disorders is the frequent occurrence of relapse episodes often caused by psychological distress and/or negative emotional affect. Relapse to drug use is commonly modeled in experimental animals using the reinstatement procedure. In this paradigm, animals are first trained to self-administer drugs of abuse via operant responding (e.g. lever-press), and then this responding is "extinguished" by withholding drug infusions. Once extinguished, responding can be "reinstated" by exposing the animal to various stimuli, including stress. However, the stressors typically used to reinstate cocaine-seeking behavior in animals are physical or pharmacological in nature, whereas psychosocial stressors more closely resemble the types of stress that typically induce craving and provoke relapse in humans. This is of great concern because numerous studies have indicated that the brain circuitry mediating responses to psychosocial stress may be different from those that mediate responses to other forms of stress. To address this gap in drug abuse research, I developed a novel reinstatement procedure in which cocaine-seeking behavior in rats is triggered by psychosocial, rather than physical or pharmacological, stress. The psychosocial stressor employed in this paradigm is conspecific social defeat, which can be engendered by placing an "intruder" rat into the home cage of a larger "resident" territorial rat. The "resident" will quickly threaten and ultimately foce the "intruder" to submit. Importantly, the distress experienced by the intruder is thought to closely mirror the types of psychosocial stress that drug abusers experience prior to a relapse episode. I hypothesize that psychosocial stress-induced cocaine seeking is mediated by distinct neural circuitry as compared to other stressors, and likely includes components of a highly- conserved "defensive" system in the brain. In Aim 1 (K99 phase), I will use c-fos immunohistochemical techniques to map the brain activation patterns produced by cocaine seeking in response to psychosocial or physical stress to identify those regions selectively activated during psychosocial stress-induced reinstatement. In Aims 2 and 3 (R00 phase), I will use the training I acquired during the K99 phase to apply chemical genetic approaches (site-specific expression of designer receptors, DREADDs) to determine whether components of the defensive circuit are causally linked to the observed drug-seeking response. The results of these studies could have a profound impact on our understanding of the interaction between stress and addiction processes, and will lay the foundation for future work aimed at further characterizing the neurobiology underlying psychosocial stress-induced drug-seeking behavior. The ultimate goal of these studies is to identify novel behavioral and/or pharmacotherapeutic treatment strategies to prevent stress-induced drug relapse.