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.

项目摘要/摘要 毒瘾是一种慢性复发性疾病，通常会对成瘾者造成毁灭性的后果。 个人和社会作为一个整体。特别是，在戒毒期间，与毒品有关的刺激或 一般的压力感觉可能会在药物依赖者中引发强烈的渴望。的确，压力 是一个特别有效的触发因素，因为不同于毒品线索(例如，用具)和上下文(即， 获得或使用药物)，这是可以避免的，压力在诸如工作的非药物环境中是不可避免的， 家庭，或经济状况。在大多数情况下，这些紧张的遭遇是令人厌恶和不可避免的，而且可能 创造一种高度焦虑的状态，上瘾的人试图通过再次吸毒来缓解这种状态 这一集。然而，与这些不可避免的压力源相反，在某些情况下是有可能控制的 在一个令人厌恶的情况下。这些可控的压力源，虽然仍然令人厌恶，但已被证明 赋予受试者应对未来应激源的跨情境韧性。在应激源的动物模型中 在可控性方面，大鼠可以旋转轮子来终止令人厌恶的尾部冲击波(可躲避的冲击波；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 认为这种冲击是不可避免的。在一次ES训练后，大鼠在恐惧中表现出较低的恐惧反应性 与IS受试者相比，条件化的社会失败甚至是非应激控制。虽然很多都是 人们知道不可控的压力源如何会加剧吸毒和复发，但关于 ES的经验可能会扭转这些负面后果。我们在这里报道，虽然老鼠有 反复的可卡因自我给药显示NAC的神经信号受损以及获得能力差 在更高级别的联想中，这些缺陷可以通过在 禁欲时期，同时也减少了绝迹中的寻药行为。这些与控制相关的效应可能源自 来自NAC、前额叶皮质(PFC)和腹侧被盖之间的一组功能重叠的回路 面积(VTA)。众所周知，这一组结构支持动机学习和压力诱导的药物复发，并且 虽然PFC对于可控性至关重要，但对于NAC或VTA是否也起到了作用，我们知之甚少 流程。为了充分描述这一现象，我将首先确定PFC中的神经信号是如何编码的 与控制相关的信息，以及这是否与动机学习和学习中恢复的功能有关 对药物复发的抵抗力。接下来，我们将利用光遗传学来确定PFC到NAC通路的必要性 在建立控制对后续学习和复发的类似神经保护作用方面。最后，我将使用 TH：：CRE大鼠以确定多巴胺信号是否对获得和后来表达 动机和复发中与控制相关的好处。这些发现表明，可控性可能提供一种 潜在的治疗干预具有临床意义，同时也提供了对神经的强大洞察力 在吸毒和吸毒幼稚人群中支持压力、成瘾和恢复能力的回路。