Neurobiological Mechanisms Underlying Stress-Induced Changes in Opiate Reward

压力引起的阿片奖励变化的神经生物学机制

基本信息

批准号：
9352306
负责人：
Michelle Suzanne Mazei-Robison
金额：
$ 33.64万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9352306
关键词：
Address Behavior Behavioral Biochemical Biological Assay Cells Chronic Chronic stress Comorbidity Complex Consumption Data Dendritic Spines Dependence Disease Disease model Dopamine Drug Addiction Drug usage Emotional Stress Evaluation FRAP1 gene Face Health Intake Intervention Knowledge Link LoxP-flanked allele Mediating Mediator of activation protein Mental disorders Modeling Molecular Mood Disorders Morphine Morphology Mus National Institute of Drug Abuse Neurons Opiate Addiction Opiates Pain Pain management Pharmaceutical Preparations Pharmacological Treatment Positioning Attribute Predisposition Proto-Oncogene Proteins c-akt Public Health Recording of previous events Regulation Research Rewards Rodent Model Role Signal Pathway Signal Transduction Sirolimus Social Interaction Stress Structure Trauma Variant Ventral Tegmental Area Viral Western Blotting Work addiction anxiety-like behavior density depressive symptoms dopaminergic neuron interest neuroadaptation neurobiological mechanism neuronal cell body new therapeutic target novel opioid abuse overexpression pre-clinical preference prevent public health relevance response social stressor

项目摘要

DESCRIPTION (provided by applicant): Despite the widespread use of opiate drugs, neuroadaptations that underlie opiate abuse remain obscure, limiting treatment. Treatment is further complicated by the presence of comorbid mood disorders, with little known about the molecular mechanisms contributing to comorbidity. This knowledge gap is problematic, as rodent models of mood disorders often employ physical stressors that confound study of pain-relieving opiate drugs. This proposal aims to use chronic emotional stress, a novel variant of the chronic social defeat stress model, to eliminate physical trauma in order to investigate the role of mammalian target of rapamycin complex 2 (TORC2) signaling in stress-induced changes in opiate reward and consumption. TORC2 is a critical mediator of morphine-induced changes in ventral tegmental area (VTA) dopamine (DA) neuron activity and morphology that alter reward behavior, and is also favorably positioned to mediate stress-induced changes in reward. This proposal will address the central hypothesis that VTA TORC2 signaling controls stress-induced changes in morphine reward and consumption and alters VTA DA neuron structure by completing the following Aims, which utilize behavioral, biochemical, and morphological approaches. Specific Aim 1 will provide a comprehensive, temporal determination of the effect of chronic emotional stress on morphine reward using conditioned place preference and voluntary two-bottle choice assays and VTA TORC2 signaling via western blot. Specific Aim 2 will determine whether VTA TORC2 signaling is necessary and sufficient for stress-induced changes in morphine reward by utilizing viral constructs that overexpress Rictor to increase VTA TORC2 signaling and floxed-Rictor mice to decrease DA cell TORC2 signaling. Specific Aim 3 will evaluate the effects of morphine and emotional stress on VTA DA neuron morphology, including the role of TORC2 signaling, by examination of VTA DA soma size and dendritic spine density. Preliminary data find that emotional stress bidirectionally alters morphine reward, decreasing intake during, and increasing intake following stress. Reward changes correlate with VTA TORC2 signaling, which is initially decreased, then increased post-stress. Novel data show that emotional stress induces a long-lasting increase in morphine reward, with a negative correlation between social interaction and morphine preference, indicating that depressive-like behavior increases morphine reward. Finally, data show that chronic stress decreases VTA DA soma size similarly to chronic morphine, a morphological change that is correlated with altered VTA DA neuronal activity and reward behavior, and has been previously shown to be mediated by decreased TORC2 signaling. Completion of these studies will establish bidirectional TORC2 signaling as a mediator of stress- induced changes in morphine reward and structural plasticity, identifying a novel signaling pathway and mechanistic approach for pharmacological treatment of opiate dependence and comorbid mood disorders.

描述（由申请人提供）：尽管阿片类药物被广泛使用，但阿片类药物滥用背后的神经适应仍然不清楚，由于共病情绪障碍的存在，治疗变得更加复杂，而对导致共病的分子机制知之甚少。知识差距是有问题的，因为情绪障碍的啮齿动物模型经常使用身体压力源，这会混淆止痛阿片类药物的研究。该提案旨在使用慢性情绪压力，这是慢性社交失败压力的一种新变体。模型，消除身体创伤，以研究哺乳动物雷帕霉素靶点复合物 2 (TORC2) 信号在应激诱导的阿片奖励和消耗变化中的作用，TORC2 是吗啡诱导的腹侧被盖区 (VTA) 变化的关键介质。 ) 多巴胺 (DA) 神经元活动和形态会改变奖赏行为，并且也有利于介导应激引起的奖赏变化。该提案将解决 VTA TORC2 信号控制的中心假设。压力引起的吗啡奖赏和消耗的变化，并通过完成以下目标来改变 VTA DA 神经元结构，其中利用行为、生化和形态学方法，具体目标 1 将提供慢性情绪压力对吗啡影响的全面、暂时的确定。使用条件位置偏好和自愿两瓶测定选择的奖励以及通过蛋白质印迹的 VTA TORC2 信号传导将确定 VTA TORC2 信号传导对于应激诱导的变化是否是必要和充分的。通过利用过度表达 Rictor 的病毒结构来增加 VTA TORC2 信号传导和 floxed-Rictor 小鼠来减少 DA 细胞 TORC2 信号传导来获得吗啡奖励具体目标 3 将评估吗啡和情绪压力对 VTA DA 神经元形态的影响，包括 TORC2 信号传导的作用。，通过检查 VTA DA 胞体大小和树突棘密度，初步数据发现情绪压力会双向改变吗啡奖励，减少摄入量并增加摄入量。压力后奖励的变化与 VTA TORC2 信号相关，压力后该信号最初减少，然后增加。新的数据表明，情绪压力会导致吗啡奖励的长期增加，这表明社交互动和吗啡偏好之间呈负相关。最后，数据显示，与慢性吗啡类似，慢性压力会降低 VTA DA 体的大小，这种形态变化与 VTA DA 神经元活动和奖励行为的改变相关。之前已被证明是由 TORC2 信号传导减少介导的。这些研究的完成将建立双向 TORC2 信号传导作为应激诱导的吗啡奖励和结构可塑性变化的调节剂，从而确定阿片类药物治疗的新信号传导途径和机制方法。依赖性和共病情绪障碍。