Reversing Cocaine-induced Impairments in the NAc with Controllable Stressors

用可控压力源逆转可卡因引起的 NAc 损伤

• 批准号: 10682741
• 负责人: Michael Saddoris
• 金额: $ 7.59万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10682741
• 关键词: Abstinence; Affect; American; Animal Model; Animals; Behavior; Behavior Control; Behavioral; Bilateral; Brain; Brain region; Cause of Death; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chronic; Clinical; Cocaine; Cognitive; Cognitive deficits; Country; Cues; Discrimination; Disease; Dopamine; Drug Addiction; Drug abuse; Drug resistance; Electrophysiology (science); Epidemic; Exposure to; Extinction (Psychology); FDA approved; Family; Feeling; Food; Food Patterns; Fright; Future; Habits; Halorhodopsins; Impairment; Individual; Intervention; Learning; Link; Mediating; Modeling; Motivation; Neurons; Neurophysiology - biologic function; Nucleus Accumbens; Occupations; Optics; Overdose; Pathway interactions; Persons; Pharmaceutical Preparations; Phase; Play; Population; Predisposition; Prefrontal Cortex; Probability; Process; Property; Rattus; Recording of previous events; Recovery; Relapse; Reporting; Role; Shock; Signal Transduction; Social Conditions; Societies; Stimulus; Stress; Stressful Event; Structure; Tail; Testing; Therapeutic; Therapeutic Intervention; Ventral Tegmental Area; Vietnam; Work; addiction; anxiety states; base; behavioral outcome; cocaine self-administration; combat; conditioned fear; conditioning; craving; dopaminergic neuron; drug abstinence; drug craving; drug of abuse; drug relapse; experience; experimental study; in vivo; insight; loved ones; neural circuit; neurotransmission; non-drug; novel; optogenetics; predicting response; prevent; psychostimulant; public health relevance; relating to nervous system; resilience; severe mental illness; social defeat; stressor; translational model

Project Summary / Abstract Drug addiction is a chronically relapsing disorder that often has devastating consequences for the addicted person and society as a whole. In particular, during periods of drug abstinence, drug-associated stimuli or general feelings of stress may elicit powerful feelings of craving in drug-dependent individuals. Indeed, stress is a particularly potent trigger because, unlike drug cues (e.g., paraphernalia) and contexts (i.e., places where drugs are obtained or used) which can be avoided, stress is unavoidable in non-drug contexts such as work, family, or finances. In most conditions, these stressful encounters are aversive and unavoidable, and can create a heightened anxiety state that addicted individuals attempt to alleviate by relapse to a drug-taking episode. However, in contrast to these inescapable stressors, in some situations it is possible to have control over an aversive situation. These controllable stressors, while still aversive, nonetheless have been shown to endow subjects with trans-situational resilience against future stressors. In an animal model of stressor controllability, rats can rotate a wheel to terminate an aversive tailshock (escapable shock; ES). Physically yoked animals receive the same shocks as the ES subjects, but are unable to control the experience, and thus perceive the shock as inescapable (IS). After a single ES session, rats show decreased fear reactivity in fear conditioning, conditioned social defeat compared to IS subjects and even non-stressed controls. While much is known about how uncontrollable stressors can potentiate drug-taking and relapse, little is known about whether ES experience may reverse these negative consequences. Here we report that while rats with a history of repeated cocaine self-administration display impaired neural signaling in the NAc as well as poor acquisition of higher-order associations, these deficits can be prevented or reversed by a single ES experience during the abstinence period, while also decreasing drug seeking in extinction. These control-related effects may derive from functionally overlapping set of circuits between the NAc, prefrontal cortex (PFC) and ventral tegmental area (VTA). This set of structures is known to support motivated learning and stress-induced drug relapse, and while PFC is critical for controllabilty, less is known about whether NAc or VTA also contribute to these processes. To fully characterize this phenomenon, I will first identify how neural signaling in the PFC encodes control-related information and whether this is related to recovered function in motivated learning and resistance to drug relapse. Next, we will use optogenetics to determine the necessity of PFC-to-NAc pathways in establishing the neuroprotective-like effects of control on subsequent learning and relapse. Finally, I will use TH::cre rats to determine whether dopamine signaling is critical for the acquisition and later expression of control-related benefits in motivation and relapse. These findings suggest that controllability may provide a potential therapeutic intervention with clinical implications, while also providing powerful insights into the neural circuits that support stress, addiction and resilience in both drug-experienced and drug-naïve populations.

项目概要/摘要 吸毒成瘾是一种慢性复发性疾病，通常会给吸毒者带来毁灭性的后果 个人和整个社会。特别是在戒毒期间，与药物相关的刺激或 普遍的压力感可能会引起药物依赖者强烈的渴望感。确实，压力 是一个特别有效的触发因素，因为与药物线索（例如用具）和环境（即发生的地方）不同 获得或使用毒品）是可以避免的，在非毒品环境中，例如工作、压力是不可避免的 家庭，或者财务。在大多数情况下，这些充满压力的遭遇是令人厌恶的且不可避免的，并且可以 造成一种高度的焦虑状态，成瘾者试图通过重新吸毒来缓解这种状态 插曲。然而，与这些不可避免的压力源相反，在某些情况下，可以控制 在令人厌恶的情况下。这些可控的压力源虽然仍然令人厌恶，但已被证明可以 赋予受试者针对未来压力源的跨情境弹性。在应激源动物模型中 可控性方面，大鼠可以旋转轮子来终止令人厌恶的尾震（可逃避的电击；ES）。身体上 带轭的动物受到与 ES 受试者相同的电击，但无法控制这种体验，因此 认为震惊是不可避免的（IS）。单次 ES 治疗后，大鼠在恐惧中表现出恐惧反应性下降 条件反射，与 IS 受试者相比，条件反射的社会失败，甚至是无压力的对照。虽然很多是 尽管人们知道无法控制的压力源如何会加剧吸毒和复发，但人们对是否会加剧吸毒和复吸知之甚少。 ES的经历或许可以扭转这些负面后果。在这里，我们报告说，虽然老鼠有 重复自我注射可卡因显示 NAc 中的神经信号受损以及获取能力较差 在高阶关联中，这些缺陷可以通过在 禁欲期的同时，也减少了寻毒的次数。这些与控制相关的影响可能会产生 来自 NAc、前额皮质 (PFC) 和腹侧被盖之间功能重叠的一组电路 区域（VTA）。众所周知，这套结构可以支持主动学习和压力引起的药物复发，并且 虽然 PFC 对于可控性至关重要，但 NAc 或 VTA 是否也会对这些影响知之甚少 流程。为了充分描述这一现象，我将首先确定 PFC 中的神经信号如何编码 控制相关信息以及这是否与动机学习中的恢复功能有关 抵抗药物复发。接下来，我们将利用光遗传学来确定PFC-to-NAc途径的必要性 建立控制对后续学习和复发的类似神经保护作用。最后，我将使用 TH::cre 大鼠确定多巴胺信号传导对于获得和随后的表达是否至关重要 与控制相关的动机和复发的好处。这些发现表明可控性可能提供 具有临床意义的潜在治疗干预，同时也提供了对神经功能的深入见解 支持有吸毒经验和未吸毒人群的压力、成瘾和恢复能力的回路。