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：
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
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/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

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的疾病，通常会对上瘾产生毁灭性的后果整个人与社会。特别是，在戒毒期间，与药物相关的刺激或一般的压力感觉可能会引起毒品依赖人的强烈渴望。确实，压力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。在大多数情况下，这些压力很大的遭遇是厌恶和不可避免的，可以建立一个更高的焦虑状态，增加个人试图通过退休来减轻毒品插曲。但是，与这些不可避免的压力源相反，在某些情况下，可以控制在厌恶的情况下。这些受控的压力源虽然仍然厌恶，但仍证明赋予对未来压力源的跨阳性韧性。在压力源的动物模型中可控性，大鼠可以旋转车轮以终止厌恶的尾垫（可逃避冲击； ES）。身体上被轭的动物受到与ES受试者相同的冲击，但无法控制体验，因此将电击视为不可避免的（IS）。一次ES会话后，大鼠在恐惧中表现出恐惧的反应性降低与受试者甚至没有压力的控制相比，条件，有条件的社交失败。虽然很多知道不可控制的压力源如何潜在的吸毒和缓解措施，知之甚少 ES经验可能会扭转这些负面后果。在这里我们报告，虽然大鼠有历史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，这些定义可以被单一的ES经验预防或反转节制期，同时还减少了寻求延长的药物。这些与控制相关的效果可能会导致从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）。已知这组结构支持成熟的学习和压力引起的药物缓解，以及虽然PFC对于控制控制至关重要，但对NAC还是VTA是否也有助于这些过程。为了充分表征这种现象，我将首先确定PFC中的神经信号传导如何编码与控制相关的信息以及这是否与动机学习中的恢复功能有关抵抗药物缓解。接下来，我们将使用光遗传学来确定PFC到NAC途径的必要条件在建立控制对随后的学习和救济的神经保护样影响时。最后，我会使用 Th :: Cre Cre大鼠确定多巴胺信号传导是否对获取和后来的表达至关重要与控制相关的动机和救济方面的好处。这些发现表明可控性可能会提供潜在的治疗干预具有临床意义，同时还为神经提供强大的见解支持药物经验和药物不接受药物的压力，成瘾和韧性的电路。