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

项目摘要/摘要 严重抑郁障碍(MDD)患者的快感缺乏症经常对可用药无效 心理社会和药物治疗，与明显的残疾以及 自杀的风险。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时间的 暴露在压力下(即“应激性快感缺乏”)，表现为慢性行为抑制和失败 去追求回报。应激性快感缺失的一种机制是谷氨酸功能的改变 在内侧前额叶皮质(MPFC)。为了在人类身上研究这一假设，我们最近进行了一系列研究 使用单体素磁共振波谱测量急性脑缺血前后mPFC中谷氨酸的研究进展 压力挑战。我们发现，在低水平应激的健康对照组中，mPFC谷氨酸水平增加，但 在高水平应激的对照组中，谷氨酸反应降低。有趣的是，在未用药的MDD中 患者中，我们发现应激后mPFC谷氨酸没有变化或增加。这改变了mPFC MDD患者对应激的谷氨酸反应反过来与对未来的负面期望相关 因此，这可能是一种机制，通过这种机制，慢性压力会转化为报酬估值受损 动力减弱。与这一概念一致的是，NMDA受体拮抗剂氯胺酮已被证明 在临床前和临床研究中改善非享乐症状。然而，mPFC和mpfc的作用 MDD谷氨酸应激反应改变的其他区域及其与RDoC正价的关系 快感缺乏症的基础结构尚未完全确立。此外，这一逆转是否改变了 MDD中的谷氨酸反应是氯胺酮对快感缺失影响的基础，目前尚不清楚。因此，当前的 提案寻求使用全脑多模式3D超高分辨率光谱磁共振(SMRI)和功能磁共振 与奖励价值和检查谷氨酸反应的动机相关的RDoC结构的评估 快感缺乏前后应激及其与症状和神经认知因素的关系 氯胺酮在MDD患者中的应用我们将使用一种新的SMRI序列来测量谷氨酸之前和 对60名健康对照组和80名MDD患者进行急性应激源刺激和非应激对照。在基线之后 扫描后，MDD患者将被随机接受单剂量静脉注射氯胺酮或安慰剂，以及 在24小时和2周内完成随访扫描。通过建立一种改变的谷氨酸对压力的反应 慢性应激的非享乐效应和氯胺酮逆转的机制，这些数据将能够 为其他针对谷氨酸系统的药物药物治疗提供药物发现平台 应激性快感缺乏症。

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.