Mechanisms underlying the influence of stress on drug-seeking behavior

项目摘要/摘要 有效管理物质使用障碍(SUDS)需要采取干预措施，将复发风险降至最低。 压力是导致复发的一个麻烦因素，因为它在肥皂症患者的生活中无处不在，不可避免。 然而，压力对复发的贡献是复杂的。而在极端情况下，应激源是直接的 引发复发，更常见的是，它们与其他刺激相互作用，为寻求毒品铺平了道路。这 Proposal研究了在肥胖症和肥胖症中调节压力的舞台效应的机制和途径 研究使用可卡因时产生的依赖于使用的神经适应，从而建立应激刺激。 作为复发的“触发者”，而不是“舞台策划者”--这是上瘾过程中的一个关键转折点。我们 已经建立了一个大鼠模型，用于研究应激对可卡因寻找的舞台设置效应。跟随 自我管理在每日访问受限(14 x 2小时/天)的条件下，压力不会恢复 扑灭了可卡因的寻找，反而加强了恢复到其他阈值以下的可卡因激发 剂量，在男性和女性身上观察到的效果，需要升高皮质酮和内源性大麻素 通过CB1受体在前额叶皮质(PL-PFC)传递信号。我们假设应激源诱导的 脑皮质酮水平的升高通过快速、快速、 糖皮质激素受体不依赖的膜相关机制，从而动员内源性大麻素， 2-花生三醇，并产生CB1R依赖的抑制PL-PFC释放GABA的作用 中间神经元。此外，我们假设，失去对PL-PFC投射通路的抑制控制 有助于寻找毒品，通过兴奋性输入激活它们，从而加强对可卡因的寻求。 该提案进一步描述了这一机制(目标1)，并试图确定PL-PFC输出路径 调节压力增强的药物寻求(目标2)。压力对可卡因寻求改变的贡献 可卡因的使用模式。与在有限的药物获取后观察到的情况相反，每天更长的时间 可卡因自我给药(每天14×6小时)建立了应激源，作为恢复的直接触发因素。这 转换涉及CRF的招募，调节投射到PL的腹侧被盖区神经元。 PFC，部分是通过增加VTA CRF-R1的表达。我们假设压力相关的适应 投射PL的VTA神经元中的信号通路建立了对药物寻找的应激源控制，代表着 肥皂泡发展的关键一步。这一假设在目标3中得到了验证。拟议的工作具有巨大的潜力 指导新的药物治疗方法，了解压力对可卡因使用的影响 在不同的使用者亚群和成瘾严重程度之间存在差异，具有重要的临床意义。最后，我们 找出压力可以改变PFC功能的新机制--这一发现对 了解压力对一系列健康/适应和病理性/适应不良行为的影响。

PROJECT SUMMARY/ABSTRACT The effective management of substance use disorders (SUDs) requires interventions that minimize relapse risk. Stress is a troublesome contributor to relapse, as it is pervasive and unavoidable in the lives of those with SUDs. However, the contribution of stress to relapse is complex. While in extreme cases stressors serve as direct triggers for relapse, more commonly they interact with other stimuli to set the stage for drug seeking. This proposal examines the mechanisms and pathways that mediate the stage-setting effects of stress in SUDs and investigates the use-dependent neuroadaptations that emerge with cocaine use that establish stressful stimuli as “triggers”, rather than a “stage setters”, for relapse – a key transition point in the progression to addiction. We have established a rat model for investigating the stage-setting effects of stress on cocaine seeking. Following self-administration under conditions of limited daily access (14 x 2 hrs/day), stress does not reinstate extinguished cocaine seeking but rather potentiates reinstatement to an otherwise subthreshold cocaine priming dose, an effect that is observed in males and females and requires elevated corticosterone and endocannabinoid signaling via the CB1 receptor in the prelimbic prefrontal cortex (PL-PFC). We hypothesize that stressor-induced increases in brain corticosterone levels promote Gq G-protein signaling in PL-PFC pyramidal neurons via a rapid, glucocorticoid receptor-independent, membrane-associated mechanism, thus mobilizing the endocannabinoid, 2-arachodonoylgycerol, and producing CB1R-dependent attenuation of GABA release from PL-PFC interneurons. Further, we hypothesize that the loss of inhibitory control of PL-PFC projection pathways that contribute to drug seeking primes them for activation by excitatory inputs, thus potentiating cocaine seeking. This proposal further characterizes this mechanism (Aim 1) and seeks to identify the PL-PFC output pathways that mediate stress-potentiated drug seeking (Aim 2). The contribution of stress to cocaine seeking changes with the pattern of cocaine use. In contrast to what is observed following limited drug access, more prolonged daily cocaine self-administration (14 x 6 hrs/day) establishes stressors as direct triggers for reinstatement. This transition involves the recruitment of CRF regulation of ventral tegmental area neurons that project to the PL- PFC, in part through increased VTA CRF-R1 expression. We hypothesize that adaptations in stress-related signaling pathways in PL-projecting VTA neurons establish stressor control over drug seeking, representing a key step in the progression of SUDs. This hypothesis is tested in Aim 3. The proposed work has great potential to guide novel pharmacotherapeutic approaches and understanding how the influence of stress on cocaine use varies among subpopulations of users and with addiction severity has important clinical implications. Finally, we identify a novel mechanism through which stress can alter PFC function – a finding that has significance for understanding the influence of stress on a range of healthy/adaptive and pathological/maladaptive behaviors.