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.

项目概要/摘要 药物滥用障碍 (SUD) 的有效管理需要采取干预措施，最大限度地降低复发风险。 压力是导致复发的一个麻烦因素，因为它在 SUD 患者的生活中普遍存在且不可避免。 然而，压力对复发的影响是复杂的，而在极端情况下，压力源是直接的。 触发复发，更常见的是它们与其他刺激相互作用，为寻求药物奠定基础。 该提案研究了调节 SUD 中压力的阶段设置效应的机制和途径，以及 研究可卡因使用产生的依赖于使用的神经适应，从而产生压力刺激 是旧瘾复发的“触发因素”，而不是“舞台设定者”——这是我们走向成瘾的关键过渡点。 建立了一个老鼠模型来研究压力对可卡因寻求的阶段性影响。 在每日访问有限（14 x 2 小时/天）的情况下进行自我管理，压力不会恢复 消除可卡因寻求，而是增强恢复阈下可卡因启动 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 通过前边缘前额皮质 (PL-PFC) 中的 CB1 受体发出信号。 大脑皮质酮水平的增加通过快速、 糖皮质激素受体独立的膜相关机制，从而动员内源性大麻素， 2-花生四烯酰甘油，并产生 CB1R 依赖性的 PL-PFC GABA 释放衰减 此外，我们还担心 PL-PFC 投射通路的抑制控制的丧失会导致 对药物寻求的贡献使它们通过兴奋性输入而激活，从而增强对可卡因的寻求。 该提案进一步描述了该机制（目标 1），并寻求确定 PL-PFC 输出路径 介导压力增强的药物寻求（目标 2）。 与有限吸毒后观察到的可卡因使用模式相比，每天的使用时间更长。 可卡因自我给药（14 x 6 小时/天）将压力源确定为恢复的直接触发因素。 转变涉及招募投射到 PL- 的腹侧被盖区神经元的 CRF 调节 PFC，部分是通过增加 VTA CRF-R1 表达来实现的，我们认为这种适应与压力相关。 PL 投射的 VTA 神经元中的信号通路建立了对药物寻求的压力源控制，代表了 SUD 进展的关键一步。该假设在目标 3 中得到检验。拟议的工作具有巨大的潜力。 指导新的药物治疗方法并了解压力对可卡因使用的影响 不同的用户亚群之间存在差异，并且成瘾严重程度具有重要的临床意义。 确定压力可以改变 PFC 功能的新机制——这一发现对于 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。