A synaptic substrate for ketamine-mediated amelioration of stress-induced anhedonia

氯胺酮介导的改善应激性快感缺失的突触底物

• 批准号: 10684093
• 负责人: Marco Pignatelli
• 金额: $ 38.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684093
• 关键词: AMPA Receptors; Acute; Address; Affect; Anesthetics; Anhedonia; Antidepressive Agents; Atrophic; Behavior; Behavioral; Brain; Cells; Chronic stress; Clinical; Consensus; DRD2 gene; Data; Dendritic Spines; Dissection; Dose; Drug usage; Electrophysiology (science); Elements; Exposure to; Functional disorder; Genetic; Glutamates; Goals; Guanosine Triphosphate Phosphohydrolases; Homosynaptic Depression; Hour; Ketamine; Knock-in Mouse; Laboratory Animals; Link; Literature; Major Depressive Disorder; Medial; Mediating; Mental Depression; Molecular; Molecular Target; Morbidity - disease rate; Motivation; Mus; NMDA receptor antagonist; Neurons; Nucleus Accumbens; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiology; Population; Prefrontal Cortex; Protein Biosynthesis; Protein Synthesis Inhibition; Proteins; Resistance; Rewards; Slice; Specific qualifier value; Stress; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Technology; Testing; Transgenic Mice; Treatment Efficacy; antagonist; antidepressant effect; behavioral outcome; burden of illness; cell type; depressive symptoms; design; disability; experimental study; genetic approach; improved; in vivo; innovation; insight; interest; mortality; neurotransmission; new therapeutic target; novel; optogenetics; pharmacologic; pleasure; pre-clinical; prevent; promoter; public health priorities; rational design; reward circuitry; spatiotemporal; synaptogenesis; therapeutic target; transmission process

SUMMARY Depression is a leading cause of morbidity and mortality worldwide and it is projected to become the second leading cause of disability by 2030. Despite these results indicate the urgent need to address depression as a public-health priority to reduce disease burden and disability, current pharmacotherapies for depression require prolonged administration (weeks if not months) for clinical improvement and they are often associated with high non-response rate. In contrast, recent clinical evidence has shown that a single sub-anesthetic dose of ketamine induces a robust and rapid (within matter of hours) antidepressant effect in 70% of treatment-resistant patients. Notably, ketamine is the first rapid-acting antidepressant with efficacy for treatment-resistant symptoms of major depression disorder such as anhedonia. Anhedonia, defined as diminished pleasure from, or interest in, previously rewarding activities is commonly precipitated by exposure to chronic stress and it is well suited to study in laboratory animals. Whereas ketamine’s primary molecular target is under debate, there is broad consensus in the literature that activation of the AMPAR as well as induction of synaptogenesis driven by de novo protein synthesis-dependent mechanisms are required for ketamine’s ability to ameliorate stress-induced anhedonia. Nevertheless, major technical barriers have hindered a circuit and synaptic-level dissection of such mechanisms. Therefore, understanding the detailed circuit and synaptic mechanisms and establishing a causal link between ketamine- evoked AMPAR-mediated synaptic plasticity and specific behavioral outcomes is crucial for designing novel and safer therapeutic targets. Here, we will tackle this question by using electrophysiology, optogenetics and recently developed technologies that offer the unprecedented opportunity to block AMPAR as well as de novo protein synthesis within genetically specified cells. Accordingly, the following hypotheses will be tested: (i) increased AMPAR-mediated synaptic transmission on D1-MSNs mediates the anti-anhedonic effects of ketamine, (ii) mPFC->NAc input is necessary for ketamine-mediated amelioration of stress-induced anhedonia, and (iii) ketamine-induced de novo protein synthesis-dependent plasticity in D1-MSNs drives ketamine-mediated amelioration of stress-induced anhedonia. Altogether, results from these studies will increase our understanding of the mechanisms of action of ketamine and might lead to new potential targets to treat stress-induced anhedonia.

摘要 抑郁症是世界范围内发病率和死亡率的主要原因，预计它将成为第二大病因 到2030年成为导致残疾的主要原因。尽管这些结果表明迫切需要将抑郁症作为一种 降低疾病负担和残疾的公共卫生优先事项，目前治疗抑郁症的药物疗法要求 延长服药时间(如果不是几个月的话也是几周的话)以改善临床状况，它们通常与高 无回应率。相比之下，最近的临床证据表明，单次亚麻醉剂剂量的氯胺酮 在70%的耐药患者中产生强劲而迅速的(数小时内)抗抑郁效果。 值得注意的是，氯胺酮是第一种快速有效的抗抑郁药物，对主要 抑郁症，如快感缺乏症。快感缺乏症，定义为对…的快感或兴趣减弱 以前有回报的活动通常是由于暴露在长期压力下而导致的，这很适合 在实验动物身上进行研究。 尽管氯胺酮的主要分子靶点仍在争论中，但文献中已达成广泛共识 依赖从头合成蛋白驱动AMPAR的激活和突触形成的诱导 氯胺酮改善应激性快感缺乏症的能力需要机制。尽管如此，少校 技术障碍阻碍了对这种机制的回路和突触水平的剖析。因此， 了解详细的电路和突触机制，并建立氯胺酮- 诱发的AMPAR介导的突触可塑性和特定的行为结果对于设计新的和 更安全的治疗靶点。在这里，我们将利用电生理学、光遗传学和最近的 开发的技术提供了前所未有的机会来阻断AMPAR以及从头开始蛋白 在基因指定的细胞内合成。因此，将检验以下假设：(一)增加 D_1-MSN上AMPAR介导的突触传递介导氯胺酮的抗快感作用，(II) MPFC-&NAC对于氯胺酮介导的改善应激性快感缺失是必要的，以及(Iii) 氯胺酮介导的D1-MSN依赖从头合成蛋白的可塑性 改善应激性快感缺乏症。总而言之，这些研究的结果将增加我们对 氯胺酮的作用机制以及可能导致治疗应激诱导的新的潜在靶点 快感缺乏症。