Glutamatergic adaptation to stress as a mechanism for anhedonia and treatment response with ketamine

谷氨酸对压力的适应是快感缺失和氯胺酮治疗反应的机制

• 批准号: 10571930
• 负责人: Michael Tilghman Treadway
• 金额: $ 76.23万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571930
• 关键词: 3-Dimensional; Acute; Anhedonia; Animals; Anterior; Area; Attenuated; Behavior assessment; Behavioral; Behavioral inhibition; Brain; Brain imaging; Brain-Derived Neurotrophic Factor; Chronic; Chronic stress; Clinical Research; Collection; Corpus striatum structure; Data; Decision Making; Dorsal; Dose; Double-Blind Method; Event; Excitatory Amino Acid Antagonists; Exposure to; Failure; Female; Functional Magnetic Resonance Imaging; Future; Glutamates; Goals; Hippocampus; Hour; Human; Impairment; Individual; Infusion procedures; Intervention; Intravenous; Ketamine; Laboratories; Link; Machine Learning; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Measures; Medial; Mediating; Mental Health; Modeling; Motivation; NMDA receptor antagonist; Neurocognitive; Pathway interactions; Patients; Peripheral; Pharmacological Treatment; Placebos; Plasma; Positive Valence; Prefrontal Cortex; Randomized; Regulation; Research Domain Criteria; Resolution; Rewards; Risk Factors; Role; Sampling; Scanning; Series; Stress; Symptoms; System; Translating; Ventral Striatum; acute stress; biological adaptation to stress; disability; disability risk; drug discovery; expectation; follow-up; improved; multimodality; neural; neuroimaging; neuroprotection; novel; perceived stress; pharmacologic; physical conditioning; preclinical study; psychosocial; response; stressor; suicidal risk; targeted agent; treatment response; ultra high resolution

Project Summary/Abstract Anhedonia in patients with major depressive disorder (MDD) frequently fails to respond to available psychosocial and pharmacological treatments and has been robustly linked to marked disability as well as suicidal risk. A well-validated model of anhedonia suggests that anhedonia may result from prolonged exposure to stress (i.e. “stress-induced anhedonia”) as manifested by chronic behavioral inhibition and a failure to pursue rewards. One proposed mechanism of stress-induced anhedonia is alteration of glutamate function in medial prefrontal cortex (mPFC). To investigate this hypothesis in humans, we recently conducted a series of studies using single-voxel MR spectroscopy measures of glutamate in mPFC before and after an acute stress challenge. We found that mPFC glutamate increased in healthy controls with low levels of stress, but decreased glutamate responses in controls with high levels of stress. Interestingly, in unmedicated MDD patients, we found no change or an increase in mPFC glutamate following stress. This altered mPFC glutamate response to stress in MDD patients was in turn correlated with negative expectations of future events and thus may be a mechanism by which chronic stress is translated into impaired reward valuation and reduced motivation. Consistent with this notion, the NMDA receptor antagonist ketamine has been shown to improve anhedonic symptoms in both pre-clinical and clinical studies. Nevertheless, the role of mPFC and other regions in this altered glutamate stress response in MDD or its association with RDoC positive valence constructs that underlie anhedonia has yet to be fully established. Moreover, whether reversal of this altered glutamate response in MDD underlies the effects of ketamine on anhedonia is unknown. Thus, the current proposal seeks to use whole-brain multi-modal 3D ultrahigh resolution spectroscopic MRI (SMRI) and fMRI assessments of RDoC constructs related to reward valuation and motivation to examine glutamate responses to stress and its relationship with symptoms and neurocognitive correlates of anhedonia before and after a ketamine challenge in MDD patients. We will use a novel SMRI sequence to measure glutamate before and after an acute stressor and a no-stress control in 60 healthy controls and 80 MDD patients. After baseline scanning, MDD patients will be randomized to receive a single dose of intravenous ketamine or placebo, and complete follow-up scans at 24-hours and 2 weeks. By establishing an altered glutamate response to stress as a mechanism for anhedonic effects of chronic stress and its reversal by ketamine, these data will be able to serve as a drug discovery platform for other pharmacologic agents targeting the glutamate system to treat stress-induced anhedonia.

项目摘要/摘要 重度抑郁症患者（MDD）的Anhedonia经常无法对可用的反应 社会心理和药物治疗，与明显的残疾以及 自杀风险。 Anhedonia的验证模型很好，表明Anhedonia可能是由于延长而导致的 暴露于压力（即“压力诱发的阿尼多尼亚”），这表现为慢性行为抑制和失败 追求奖励。应力诱导的抗甲曲的一种提出的机制是谷氨酸功能的改变 在中位前额叶皮层（MPFC）中。为了研究人类的这一假设，我们最近进行了一系列 急性之前和之后使用单素MR光谱测量MPFC中谷氨酸的研究 压力挑战。我们发现，在压力较低的健康对照中，MPFC谷氨酸增加，但 较高压力的对照中的谷氨酸反应降低。有趣的是，在未使用的MDD中 患者，我们发现在压力下没有变化或MPFC谷氨酸的增加。这改变了MPFC 谷氨酸对MDD患者压力的反应反应又与对未来的负面预期相关 事件，因此可能是将慢性压力转化为受损奖励价值和 减少动力。与这个概念一致，NMDA接收器拮抗剂氯胺酮已显示为 改善临床前和临床研究中的Anhedonic症状。然而，MPFC和 MDD中这种改变的谷氨酸应力反应的其他区域或其与RDOC正有效性的关联 基于Anhedonia的构造尚未完全建立。此外，是否逆转这种改变 MDD中的谷氨酸反应是氯胺酮对甲于甲霉菌的作用尚不清楚的。那，电流 提案旨在使用全脑多模式3D超高分辨率光谱MRI（SMRI）和fMRI 评估与奖励价值和检查谷氨酸反应的动力有关的RDOC结构 压力及其与症状和神经认知相关的关系 MDD患者的氯胺酮挑战。我们将使用新颖的SMRI序列来测量谷氨酸 在急性应激源和60个健康对照和80名MDD患者中进行无压力控制之后。基线之后 扫描，MDD患者将被随机分配以接受一剂静脉注射氯胺酮或安慰剂，以及 在24小时和2周内完成后续扫描。通过建立对应激的谷氨酸反应的改变 慢性应激及其逆转氯胺酮逆转的机制，这些数据将能够 用作针对谷氨酸系统治疗的其他药物的药物发现平台 压力引起的抗甲氧菌。