Functional neuroanatomy underlying psychosocial stress-induced cocaine seeking

 描述（由申请人提供）：可卡因滥用和依赖性障碍的一个突出特征是经常发生复发事件，通常由心理困扰和/或负面情绪影响引起。药物使用复发通常在使用恢复程序的实验动物中建模。在这种模式中，动物首先被训练通过操作性反应（例如，按压）自我施用滥用药物，然后通过抑制药物输注来“熄灭”这种反应。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，通常用于恢复动物寻求可卡因行为的压力源本质上是物理或药理学的，而心理社会压力源更接近于通常诱导渴望并引起人类复发的压力类型。这是一个非常令人担忧的问题，因为许多研究表明，调节对心理社会压力的反应的大脑回路可能与调节对其他形式压力的反应的大脑回路不同。 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，大鼠的可卡因寻求行为是由心理社会压力而不是身体或药理压力引发的。在这种范式中采用的心理社会压力是同种社会失败，这可以通过将一个“入侵者”大鼠放入一个更大的“居民”领土大鼠的家笼中而产生。“居民”会很快威胁并最终迫使“入侵者”屈服。重要的是，入侵者所经历的痛苦被认为是吸毒者在复吸前所经历的社会心理压力的密切反映。我假设，与其他压力源相比，心理社会压力诱导的可卡因寻求是由不同的神经回路介导的，并且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），我将使用c-fos免疫组织化学技术来映射的大脑激活模式的可卡因寻求响应于心理或身体的压力，以确定这些区域选择性激活在心理社会压力诱导的恢复。在目标2和3（R00阶段）中，我将使用我在K99阶段获得的培训来应用化学遗传学方法（设计受体的位点特异性表达，DREADD）来确定防御回路的组成部分是否与观察到的药物寻求反应有因果关系。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，并将为未来的工作奠定基础，旨在进一步表征心理社会压力诱导的药物寻求行为的神经生物学基础。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.