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.

项目总结/摘要 重度抑郁症（MDD）患者的快感缺乏通常对现有的 心理社会和药物治疗，并已与明显残疾以及 自杀风险一个经过充分验证的快感缺乏模型表明，快感缺乏可能是由于长期的 暴露于应激（即“应激诱导的快感缺失”），表现为慢性行为抑制和失败 追求回报。应激性快感缺失的一个机制是谷氨酸功能的改变 内侧前额叶皮层（mPFC）。为了在人类中调查这一假设，我们最近进行了一系列 使用单体素磁共振波谱测量mPFC中谷氨酸的研究， 压力挑战我们发现，在低水平压力的健康对照组中，mPFC谷氨酸盐增加， 在高水平压力的对照组中降低谷氨酸反应。有趣的是，在未用药的MDD中， 我们发现，压力后mPFC谷氨酸没有变化或增加。这种改变的mPFC 抑郁症患者对压力的谷氨酸反应反过来与对未来的负面预期相关， 事件，因此可能是一种机制，通过这种机制，慢性压力被转化为受损的奖励价值， 减少动机。与这一观点一致，NMDA受体拮抗剂氯胺酮已被证明 改善临床前和临床研究中的快感缺失症状。尽管如此，小额供资基金的作用和 MDD中谷氨酸应激反应改变的其他区域或其与RDoC阳性价的相关性 快感缺失的基础结构尚未完全建立。此外，这种逆转是否改变了 在MDD中谷氨酸反应是氯胺酮对快感缺乏的作用的基础尚不清楚。因此电流 一项提案寻求使用全脑多模态3D高分辨率光谱MRI（SMRI）和功能MRI 与奖励评价和动机相关的RDoC结构的评估，以检查谷氨酸反应 应激及其与快感缺乏症的症状和神经认知相关因素的关系 MDD患者的氯胺酮激发。我们将使用一种新的SMRI序列来测量谷氨酸， 在60名健康对照和80名MDD患者中进行急性应激和无应激对照后。基线后 扫描时，MDD患者将随机接受单次静脉注射氯胺酮或安慰剂， 在24小时和2周时完成随访扫描。通过建立对压力的改变的谷氨酸反应， 慢性应激的快感缺失效应及其被氯胺酮逆转的机制，这些数据将能够 作为其他靶向谷氨酸系统的药物发现平台， 压力导致的快感缺失