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

基本信息

批准号：
10242170
负责人：
Michael Saddoris
金额：
$ 34.47万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
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/10242170
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

项目摘要

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 /摘要吸毒成瘾是一种长期复发性疾病，通常对地址产生毁灭性的施工后果人和整个社会。压力的普遍感觉确实会引起毒品的渴望。是一个特别有效的触发因素可以避免的药物获得或使用的药物，在工作等非药物的情况下，不可避免的压力是不可避免的。家庭或财务状况。建立一个更高的焦虑状态，增加个人试图通过复发来减轻毒品的尝试然而，与这些不可避免的压力相比，在某些情况下可以控制在厌恶的情况下。赋予对未来压力源的反态弹性。可控性，大鼠可以旋转车轮以终止厌恶的尾声（可逃避的冲击； ES）被轭的动物受到与ES受试者相同的冲击，但无法控制体验，因此将冲击视为不可避免的（IS）。与受试者和压力控制相比，条件，有条件的社交失败。知道不可控制的压力源如何增强吸毒和复发，几乎了解是否知道是否知道 ES经验可能会扭转这些负面后果。重复可卡因自我给药显示NAC中的神经信号传导受损，而对高阶关联，这些缺陷可以通过单一的ES经验来预防或逆转戒酒期，同时减少了灭绝药物的药物。从NAC，前额叶皮层（PFC）和腹侧段之间的功能重叠的电路集。区域（VTA）。虽然PFC对于控制障碍至关重要，但较少了解，而VTA也有助于这些过程。与控制相关的信息和Whis与动机学习和对药物复发的抗性。在建立控制对后续学习和复发的神经保护作用时，我将使用。 Th :: Cre Rats确定多巴胺多巴胺信号传导是否对获取和以后的表达至关重要与控制相关的动机和复发的好处。潜在的治疗干预措施具有临床意义，同时还为神经提供强大的见解在药物昂贵和不接受药物的人群中支持压力，成瘾和韧性的电路。