Mechanisms underlying the influence of stress on drug-seeking behavior

压力对药物寻求行为影响的机制

• 批准号: 10752220
• 负责人: Cecilia J Hillard
• 金额: $ 58.62万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752220
• 关键词: 2-arachidonylglycerol; Brain; CNR1 gene; Cells; Cholecystokinin; Clinical; Cocaine; Cocaine use disorder; Complex; Corticosterone; Corticotropin-Releasing Hormone; Disinhibition; Dose; Electrophysiology (science); Endocannabinoids; Female; Fiber; G alpha q Protein; Genetic; Glucocorticoid Receptor; Glucocorticoids; Individual; Intake; Interneurons; Intervention; Label; Mediating; Membrane; Modeling; Molecular; Neurons; Nucleus Accumbens; Output; Pathologic; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Photometry; Prefrontal Cortex; Process; Rattus; Regulation; Relapse; Reporter; Self Administration; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Site; Stimulus; Stress; Substance Use Disorder; Synaptic Transmission; Testing; Ventral Tegmental Area; Work; addiction; attenuation; cocaine seeking; cocaine self-administration; cocaine use; craving; dopaminergic neuron; drug seeking behavior; endocannabinoid signaling; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; maladaptive behavior; male; neuroadaptation; novel; novel therapeutics; receptor; recruit; relapse risk; response; restraint; risk minimization; stressor

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.

项目总结/摘要 物质使用障碍（SUD）的有效管理需要干预措施，最大限度地减少复发风险。 压力是复发的一个麻烦因素，因为它在SUD患者的生活中无处不在，不可避免。 然而，压力对复发的影响是复杂的。在极端情况下，压力源直接 虽然这些因素是复吸的触发因素，但更常见的是，它们与其他刺激因素相互作用，为寻求毒品奠定基础。这 该提案研究了介导SUD中压力的阶段设置效应的机制和途径， 研究可卡因使用引起的使用依赖性神经适应，从而产生压力刺激 作为“触发器”，而不是“舞台设置者”，复发-一个关键的过渡点，在进展到成瘾。我们 已经建立了一个大鼠模型，用于研究压力对可卡因寻求的阶段设置影响。以下 在有限的每日访问条件下自我给药（14 x 2小时/天），压力不会恢复 熄灭的可卡因寻求，而是增强恢复到另外的阈下可卡因启动 剂量，在男性和女性中观察到的效果，需要升高皮质酮和内源性大麻素 通过CB 1受体在前边缘前额皮质（PL-PFC）的信号。我们假设压力源引起的 脑皮质酮水平的增加通过快速， 糖皮质激素受体非依赖性，膜相关机制，从而动员内源性大麻素， 2-花生四烯酰甘油，并产生CB 1 R依赖性的从PL-PFC释放GABA的衰减 中间神经元此外，我们假设，PL-PFC投射通路的抑制控制的丧失， 对药物寻求的贡献使它们被兴奋性输入激活，从而增强可卡因寻求。 该提案进一步描述了这一机制（目标1），并试图确定PL-PFC输出途径 介导压力增强的药物寻求（目的2）。压力对可卡因寻求的影响随着 可卡因的使用模式与有限的药物获取后观察到的情况相反， 可卡因自我给药（14 x6小时/天）将紧张性刺激确立为恢复的直接触发因素。这 过渡涉及招募CRF调节腹侧被盖区神经元，投射到PL- PFC，部分通过增加VTA CRF-R1表达。我们假设与压力相关的适应 PL投射VTA神经元中的信号通路建立了对药物寻求的应激控制，代表了一种新的药物依赖。 SUD进展的关键步骤。这一假设在目标3中得到检验。拟议的工作具有很大的潜力 指导新的药理学方法，并了解压力对可卡因使用的影响， 在使用者的亚群之间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 确定了一种新的机制，通过这种机制，压力可以改变PFC功能-这一发现对 了解压力对一系列健康/适应性和病理/适应不良行为的影响。