Investigating the molecular and synaptic mechanisms which underlie the sustained antidepressant effects of NMDA receptor antagonists

在过去的几年里，由于发现氯胺酮在单次治疗后可诱导快速和持续的临床益处，对速效抗抑郁药的兴趣激增。这也导致了新的投资，不仅研究这些药物的临床效果，而且更好地了解它们的基本生物学。通过这项工作，可以开发出具有更好耐受性和更广泛临床应用的新治疗方法。虽然已知氯胺酮作为NMDA受体拮抗剂，但并非所有已进行临床试验的NMDA受体拮抗剂均表现出相同的速效抗抑郁药特征。氯胺酮的一个独特特征是，单次治疗的效果持续超过药物的初始药理学作用，表明诱导了一些有利于情绪的长期适应性变化。在这个项目中，我们与勃林格殷格翰建立了合作关系，旨在整合我们在分子、电生理和行为研究方面的综合专业知识，以试图了解这些效应背后的机制。利用我们经过验证的抑郁症情感偏见啮齿动物模型，本项目将使用我们的情感偏差测试来比较不同NMDA受体拮抗剂的急性和持续作用，临床数据和不同药物的特定药效学特性。为了将这些行为发现与潜在的机制联系起来，我们还将使用取自前额叶皮层的切片中的离体电生理学进行研究。使用荧光标记，我们将确定特定的神经元群体的输入到关键的大脑区域，杏仁核和海马，并调查是否有特定的变化，突触生理学中观察到的持续抗抑郁药的疗效在行为测定。与勃林格殷格翰合作，我们还将分析有效与无效NMDA受体拮抗剂急性治疗后这些不同神经元群体中的RNA表达谱。使用RNASeq和生物信息学，这些研究将产生对潜在机制和新型药物靶点的新见解，这些新见解将随着项目的发展而进一步探索，包括使用与靶向脑灌注和基于DREADD的方法相结合的体内行为研究。

In the last few years there has been a surge in interest in rapid-acting antidepressants arising from the discovery that ketamine induces both rapid and sustained clinical benefits following a singletreatment. This has also led to new investment not only to study the clinical effects of these drugs but also to better understand their fundamental biology. Through this work, new treatments with better tolerability and wider clinical applications may be developed. Although ketamine is known to act as an NMDA receptor antagonist, not all NMDA receptor antagonists which have been tested clinically exhibit this same rapid-acting antidepressant profile. A unique characteristic of ketamine is that the effects of a single treatment are sustained beyond the initial pharmacological effects of the drug suggesting induction of some longer-term adaptive change which benefits mood. In this project we have established a collaboration with Boehringer Ingelheim and aim to integrate our combined expertise across molecular, electrophysiological and behavioural studies to try to understand the mechanisms which underlie these effects.Capitalising on our validated rodent model of affective biases in depression, this project will use our affective bias test to compare the acute and sustained effects of different NMDA receptor antagonists comparing the results with clinical data and specific pharmacodynamic properties of the different drugs. In order to relate these behavioural findings to the underlying mechanisms we will also undertake studies using ex vivo electrophysiology in slices taken from the prefrontal cortex. Using fluorescent labelling we will identify specific neuronal populations which input to key brain regions, amygdala and hippocampus and investigate whether there are specific changes in synaptic physiology which correspond to the sustained antidepressant efficacy observed in the behavioural assays. In collaboration with Boehringer Ingelheim we will also under take analysis of the RNA expression profile within these different neuronal populations following acute treatment with efficacious versus non-efficacious NMDA receptor antagonists. Using RNASeq and bioinformatics, these studies will generate new insights into potential mechanisms and novel drug targets which will be further explored as the project develops including using in vivo behavioural studies integrated with target brain infusions and DREADDs-based methods.