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: 9789243
• 负责人: Michael Saddoris
• 金额: $ 35.5万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789243
• 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; Self Administration; 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; 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.

项目总结/摘要 药物成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 人和整个社会。特别是在药物戒断期间，药物相关刺激或 一般的压力感可能引起药物依赖者强烈的渴望感。事实上， 是一种特别有效的触发因素，因为，与药物提示不同（例如，用具）和上下文（即，的地方 获得或使用药物），这是可以避免的，压力在非药物环境中是不可避免的，如工作， 家庭或财务。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， 产生高度焦虑状态，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， 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， 赋予受试者对未来压力源的跨情境弹性。在压力源的动物模型中 在可控性方面，大鼠可以旋转轮子来终止令人厌恶的尾部电击（逃避电击; ES）。物理 负轭动物接受与ES受试者相同的电击，但无法控制体验，因此 认为冲击是不可避免的（IS）。在一个单一的ES会话后，大鼠在恐惧中表现出降低的恐惧反应， 条件反射，条件社会失败相比，是科目，甚至非强调控制。虽然很多 关于无法控制的压力源如何增强吸毒和复吸，我们所知甚少， ES的经验可能会扭转这些负面影响。在这里，我们报告说，虽然老鼠的历史， 重复的可卡因自我给药显示NAc中的神经信号传导受损， 高阶协会，这些赤字可以防止或逆转的一个单一的ES经验，在 禁欲期，同时也减少了灭绝中的药物寻求。这些与控制相关的影响可能会产生 从NAc，前额叶皮层（PFC）和腹侧被盖之间的功能重叠回路集 区域（VTA）。已知这组结构支持动机性学习和压力诱导的药物复吸， 虽然PFC对于可测量性是至关重要的，但是关于NAc或VTA是否也对这些有贡献，我们知道得很少 流程.为了充分描述这种现象，我将首先确定PFC中的神经信号如何编码 控制相关信息，以及这是否与动机性学习中的恢复功能有关， 对药物复发的抵抗。接下来，我们将使用光遗传学来确定PFC到NAc通路的必要性。 在建立控制对随后的学习和复发的神经保护作用。最后，我将使用 TH：：cre大鼠，以确定多巴胺信号传导是否对获得和随后表达 控制相关的好处在动机和复发。这些发现表明，可控性可能提供了一个 具有临床意义的潜在治疗干预，同时也为神经系统疾病提供了有力的见解。 支持有毒品经验和未吸毒人群的压力、成瘾和恢复力的回路。