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

• 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
• 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

 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）：尽管阿片类药物的广泛使用，阿片类药物滥用的神经适应仍然不清楚，限制了治疗。由于存在共病的情绪障碍，治疗变得更加复杂，对共病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使用身体压力，这混淆了止痛阿片类药物的研究。该提案的目的是使用慢性情绪压力，慢性社会失败压力模型的一种新变体，以消除身体创伤，以研究哺乳动物雷帕霉素复合物2（TORC 2）信号转导靶蛋白在阿片奖励和消费的压力诱导的变化中的作用。TORC 2是吗啡诱导的腹侧被盖区（VTA）多巴胺（DA）神经元活动和形态改变奖励行为的变化的关键介质，并且也有利地定位于介导应激诱导的奖励变化。该提案将解决中心假设，即VTA TORC 2信号控制应激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，这些目标利用行为，生物化学和形态学方法。具体目标1将提供一个全面的，时间测定慢性情绪应激对吗啡奖励的影响，使用条件性位置偏好和自愿两瓶选择测定和VTA TORC 2信号通过蛋白质印迹。具体目标2将通过利用过表达Rictor的病毒构建体来增加VTA T0RC2信号传导，并通过利用过表达Rictor的小鼠来减少DA细胞T0RC2信号传导，来确定VTA T0RC2信号传导对于吗啡奖赏中的应激诱导的变化是否是必要的和足够的。具体目标3将通过检查VTA DA索马体大小和树突棘密度来评估吗啡和情绪应激对VTA DA神经元形态的影响，包括TORC 2信号传导的作用。初步数据发现，情绪压力双向改变吗啡奖励，减少摄入量期间，并增加摄入量后的压力。奖励变化与VTA TORC 2信号相关，该信号最初减少，然后在应激后增加。新的数据表明，情绪压力会导致吗啡奖赏的长期增加，社会互动与吗啡偏好之间存在负相关，这表明抑郁样行为会增加吗啡奖赏。最后，数据显示，慢性应激降低腹侧被盖区DA索马体大小类似于慢性吗啡，形态学变化与改变的腹侧被盖区DA神经元活动和奖励行为，并已被先前显示为介导的减少TORC 2信号。这些研究的完成将建立双向TORC 2信号传导作为应激诱导的吗啡奖赏和结构可塑性变化的介体，鉴定用于阿片依赖和共病情绪障碍的药理学治疗的新信号传导途径和机制方法。