Investigating serotonergic modulation of affective biases and emotional behaviour in rodents using psychedelic drugs

使用迷幻药物研究啮齿类动物情感偏见和情绪行为的血清素调节

• 批准号: BB/V015028/1
• 负责人: Emma Robinson
• 金额: $ 95.46万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV015028%2F1
• 关键词: Investigating; serotonergic; modulation; affective; biases

Humans have used psychedelic drugs throughout their history as part of cultural practises or more recently as potential treatments for psychiatric disorders. The psychedelic experience is a unique psychological state associated with profound, positive changes in mood. There has been a resurgence in interest in the potential clinical uses for psychedelic drugs. Research into how these drugs affect the brain is also a route to better understanding the fundamental biology of emotions. Studying the brain and how it controls our behaviour is complicated and cognitive and affective behaviours represent one of the biggest challenges in neuroscience. Experiments in animals are needed to understand the specific parts of the brain, brain chemistry and drug targets involved. Animal tests are also very important for the development of knowledge about normal psychology so we can understand how and why these change in pathological states. In the context of emotional behaviour, recent research has shown it is feasible to measure relevant behaviours in rodents and this project will build on this using an assay developed in our laboratory, the affective bias test. We will use our test to investigate the interaction between biological and psychological mechanisms building on evidence that biases in cognition, termed 'affective biases', contribute to both normal and pathological emotional behaviour. Affective bias is a term used in cognitive neuroscience which describes the psychological process whereby cognition is modified by emotional state. Research has shown that negative affective biases affecting learning, memory, decision-making and interpretation, are a common feature of depression. We have recently discovered that both conventional delayed onset antidepressants and rapid-acting antidepressants modulate affective biases, but they do this in very different ways. The discovery that pharmacological treatments can induce rapid and sustained effects on mood is a major development for the field. It has led to the proposal that there is a class of small molecules which share these characteristics. Because these drugs have effects which are sustained beyond the time the drug is in the body, they must be able to generate adaptive changes and evidence suggest these plasticity changes arise within specific neural networks and has led to their collective name of 'psychoplastogens'. Psychedelics are thought to be psychoplastogens and this project will explore whether they share the ability to modify affective biases as we have observed with other drugs from this class. Our planned research will focus on the effects of two key psychedelic drugs, psilocybin and MDMA. These drugs both act on one of the brains chemical signalling pathways, serotonin, but do so in different ways. We aim to not only study their effects on behaviour but then explore how these effects arise. This will involve studies where we use specific chemicals to block components of the pathways we think are involved. We will also look at the brain regions involved by delivering the drugs directly to the region of interest. Alongside the behavioural, work we are collaborating with colleagues with expertise in recording the electrical properties of cells and adaptive changes in neuronal physiology. This will reveal how psychedelic drugs affect the properties of single cells within our regions of interest. In humans much of what we know about how drugs affect specific regions of the brain are obtained from function brain imaging (fMRI). In our final work package, we plan to use an equivalent method to fMRI known as oxygen amperometry. Using this approach, we can record oxygen use with specific brain region as an indicator of neural activity and the connections between relevant circuits. By integrating all the data obtained across these different approaches we will be able to relate the molecular/cellular and neural circuits with a relevant emotional behaviour.

人类在整个历史上一直使用迷幻药物作为文化习俗的一部分，或者最近作为精神疾病的潜在治疗方法。迷幻体验是一种独特的心理状态，与深刻、积极的情绪变化相关。人们对迷幻药物的潜在临床用途重新产生了兴趣。研究这些药物如何影响大脑也是更好地理解情绪的基本生物学的一种途径。研究大脑及其如何控制我们的行为是复杂的，认知和情感行为是神经科学中最大的挑战之一。需要在动物身上进行实验来了解大脑的特定部分、大脑化学和所涉及的药物靶标。动物实验对于正常心理学知识的发展也非常重要，因此我们可以了解这些病理状态如何以及为何发生变化。在情绪行为的背景下，最近的研究表明测量啮齿类动物的相关行为是可行的，该项目将在此基础上使用我们实验室开发的一种检测方法——情感偏差测试。我们将使用我们的测试来研究生物和心理机制之间的相互作用，其基础是认知偏差（称为“情感偏差”）会导致正常和病态的情绪行为。情感偏见是认知神经科学中使用的一个术语，它描述了认知因情绪状态而改变的心理过程。研究表明，影响学习、记忆、决策和解释的负面情感偏见是抑郁症的一个共同特征。我们最近发现，传统的延迟起效抗抑郁药和速效抗抑郁药都能调节情感偏差，但它们的作用方式却截然不同。药物治疗可以对情绪产生快速和持续的影响的发现是该领域的重大发展。由此有人提出，存在一类具有这些特征的小分子。由于这些药物的作用在药物进入体内后仍持续存在，因此它们必须能够产生适应性变化，并且有证据表明这些可塑性变化出现在特定的神经网络内，并导致它们被统称为“精神塑性剂”。迷幻药被认为是精神塑性剂，该项目将探讨它们是否具有改变情感偏见的能力，正如我们在此类药物中观察到的那样。我们计划的研究将集中于两种关键致幻药物裸盖菇素和摇头丸的作用。这些药物都作用于大脑化学信号通路之一——血清素，但作用方式不同。我们的目标不仅是研究它们对行为的影响，还要探索这些影响是如何产生的。这将涉及我们使用特定化学物质来阻断我们认为涉及的途径成分的研究。我们还将通过将药物直接输送到感兴趣的区域来观察所涉及的大脑区域。除了行为方面的工作外，我们还与在记录细胞电特性和神经元生理学适应性变化方面具有专业知识的同事合作。这将揭示迷幻药物如何影响我们感兴趣区域内单细胞的特性。对于人类来说，我们对药物如何影响大脑特定区域的了解大部分都是通过功能脑成像 (fMRI) 获得的。在我们的最终工作包中，我们计划使用与功能磁共振成像等效的方法，称为氧电流分析法。使用这种方法，我们可以记录特定大脑区域的氧气使用情况，作为神经活动和相关回路之间连接的指标。通过整合通过这些不同方法获得的所有数据，我们将能够将分子/细胞和神经回路与相关的情绪行为联系起来。

项目成果

Rapid-acting antidepressant drugs modulate affective bias in rats.

• DOI: 10.1126/scitranslmed.adi2403
• 发表时间: 2024-01-10
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Hinchcliffe JK;Stuart SA;Wood CM;Bartlett J;Kamenish K;Arban R;Thomas CW;Selimbeyoglu A;Hurley S;Hengerer B;Gilmour G;Robinson ESJ
• 通讯作者: Robinson ESJ

Pharmacological characterisation of the effort for reward task as a measure of motivation for reward in male mice.

• DOI: 10.1007/s00213-023-06420-9
• 发表时间: 2023-11
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Marangoni, Caterina;Tam, Melissa;Robinson, Emma S. J.;Jackson, Megan G.
• 通讯作者: Jackson, Megan G.