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（由适用提供）：尽管使用优化药物的广泛使用，但构成优化滥用的神经适应性仍然晦涩难懂，限制了治疗。合并情绪障碍的存在使治疗更加复杂，对有助于合并症的分子机制知之甚少。这种知识差距是有问题的，因为情绪障碍的啮齿动物模型经常采用身体压力源，这些压力源使研究疼痛的止痛药物混淆。该提案旨在使用慢性情绪压力，这是慢性社会失败压力模型的一种新型变体，以消除身体创伤，以研究雷帕霉素复合物2（TORC2）信号在压力诱导的有效奖励和消费变化中的作用。 TORC2是吗啡诱导的腹侧对盖区域（VTA）多巴胺（DA）神经元活性和形态的关键介体，它改变了奖励行为，并且在介导压力诱导的奖励变化方面也有利地定位。该提案将解决以下中心假设：VTA TORC2信号传导控制应力诱导的吗啡奖励和消耗的变化，并通过完成以下目标来改变VTA DA神经元结构，这些目标利用了行为，生化和形态学方法。特定的目标1将对慢性情绪压力对吗啡特异性目标的影响提供全面的临时确定，将评估VTA TORC2信号传导和Floxed-Rictor小鼠，以减少DA细胞Torc2信号传导。特定的目标3将通过利用过表达Richtor的病毒构建体来增加VTA TORC2信号传导和Floxed-Rictor小鼠来减少DA DA Cell Cellc2信号传导，从而评估VTA TORC2信号传导是必需的，足以使应力诱导的吗啡奖励的变化。特定的目标3将通过检查VTA DA SOMA大小和树突状脊柱密度来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。初步数据发现，情绪压力在双向上会改变吗啡的奖励，减少摄入量并在压力后增加摄入量。奖励变化与VTA TORC2信号传导相关，该信号最初会减少，然后增加应力后压力。新颖的数据表明，情绪压力会引起吗啡奖励的持久增长，社会相互作用与吗啡偏爱之间存在负相关，这表明抑郁型行为会增加吗啡奖励。最后，数据表明，慢性应激降低了VTA DA SOMA的大小类似于慢性吗啡，这种形态学变化与VTA DA神经元活性和奖励行为的改变相关，并且先前已被证明是由TORC2信号降低介导的。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介体，确定了一种新型的信号传导途径和机械方法，用于优化依赖性和合并情绪障碍的药物治疗。