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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要重度抑郁症 (MDD) 患者的快感缺失常常无法对现有药物做出反应心理社会和药物治疗与明显的残疾以及一个经过充分验证的快感缺乏模型表明，快感缺乏可能是由长期存在引起的。暴露于压力（即“压力引起的快感缺失”），表现为慢性行为抑制和失败追求奖励的一种拟议的压力引起的快感缺乏机制是谷氨酸功能的改变。为了在人类中研究这一假设，我们最近进行了一系列研究。使用单体素磁共振波谱法测量急性前额叶皮质中谷氨酸的研究我们发现，在压力水平较低的健康对照组中，mPFC 谷氨酸含量有所增加，但是高压力对照组的谷氨酸反应降低。患者，我们发现压力后 mPFC 谷氨酸没有变化或增加，这改变了 mPFC。 MDD 患者对压力的谷氨酸反应反过来又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，慢性压力会转化为受损的奖励评估和与这一观点相一致的是，NMDA 受体拮抗剂氯胺酮已被证明可以降低动机。然而，在临床前和临床研究中，mPFC 的作用和改善快感缺乏症状。 MDD 中谷氨酸应激反应改变的其他区域或其与 RDoC 正价的关联快感缺乏的基础结构尚未完全确立。 MDD 中的谷氨酸反应是氯胺酮对快感缺乏影响的基础，因此，目前尚不清楚。该提案寻求使用全脑多模态 3D 超高分辨率光谱 MRI (SMRI) 和 fMRI 与奖励评估和检查谷氨酸反应动机相关的 RDoC 构建评估压力及其与快感缺失前后症状和神经认知相关性的关系 MDD 患者的氯胺酮激发试验之前和之后，我们将使用一种新型 SMRI 序列来测量谷氨酸。在 60 名健康对照者和 80 名 MDD 患者中进行急性压力源和无压力对照后。通过扫描，MDD 患者将被随机分配接受单剂量静脉注射氯胺酮或安慰剂，并且在 24 小时和 2 周内完成后续扫描通过建立对压力的改变的谷氨酸反应。慢性压力的快感缺失效应及其通过氯胺酮逆转的机制，这些数据将能够作为针对谷氨酸系统的其他药物的药物发现平台来治疗压力引起的快感缺乏。