Unlocking the psychopharmacology of psychedelics

在过去的几年里，人们对迷幻药物的潜在临床益处的兴趣激增。这也带来了新的投资，不仅是为了研究这些药物的临床效果，也是为了更好地了解它们的基础生物学。通过这项工作，可能会开发出耐受性更好、临床应用更广泛的新疗法。有些令人惊讶的是，我们对迷幻药物的基础生物学知识仍然如此有限。尽管药物的迷幻效应已经被人类利用了数千年，直到20世纪70年代才被用于精神分裂症，但这些迷幻药物的基本生物学仍不清楚。作为天然存在的物质，这些药物具有复杂的药理作用，并与多个受体群体相互作用。并不是所有的迷幻剂都是相同的，即使是药理上的微小差异也可能对它们的行为效果产生重大影响。例如，大多数都作用于5-HT2A受体，但也作用于其他5-羟色胺受体，目前尚不清楚哪些受体或受体组合对其不同方面的影响起作用。在这个项目中，我们与Compass Path公司建立了合作关系，他们正在开发临床使用的裸盖菇素。该项目将开始使用结合电生理学、行为学和分子药理学的综合方法来解决这些悬而未决的问题。我们最初的重点将是前额叶皮质和正价系统，例如与奖励相关的行为。我们的目标是通过正常啮齿动物的行为任务来确定迷幻剂对行为的影响，这些任务映射到奖励处理的不同方面，如评估、预期和学习。具体地说，我们预测迷幻剂将对奖赏学习产生更大的影响，这可能有助于它们的持续效果。最近的成像研究和动物数据有力地支持了前额叶皮质和谷氨酸信号的直接调制的关键作用。我们将使用切片电生理学来探索这一点，并观察幼稚组织中的急性药物效应，以及在治疗后的不同时间点从动物身上采集样本。通过确定随时间发生的变化的确切性质，我们预计能够将其与行为数据相结合，以更好地解释这些药物如何以及为什么具有急性和持续的影响。一旦我们建立了更丰富的数据集，也将有机会使用更复杂的分析方法。

In the last few years there has been a surge in interest in the potential clinical benefits of psychedelic drugs. 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. It is somewhat surprising to find that our knowledge of the fundamental biology of psychedelic drugs remains so limited. Although psychedelic effects of drugs have been exploited by humans for millennia and utilised in sychiatry up until the 1970s, much about the fundamental biology of these psychedelic drugs remains unknown. As naturally occurring substances, these drugs have a complex pharmacology and interact with multiple receptor populations. Not all psychedelics are the same and even small differences in their pharmacology may have big impacts on their behavioural effects. For example, most have activity at the 5-HT2A receptor but also act at other 5-HT receptors and it is still not known which receptors or combination of receptors contribute to the different aspects of their effects. In this project we have established a collaboration with COMPASS Pathways who are developing psilocybin for clinical use. This project will start to address these unanswered questions using an integrated approach combining electrophysiological, behavioural and molecular pharmacology. Our initial focus will be the prefrontal cortex and the positive valence system, e.g. reward-related behaviours. We aim to establish the behavioural effects of psychedelics using behavioural tasks in normal rodents that map onto different aspects of reward processing, such as valuation, anticipation and learning. Specifically, we predict that psychedelics will have greater effects on reward learning which may contribute to their sustained effects. Recent imaging studies as well as animal data strongly support a key role for the prefrontal cortex and direct modulation of glutamate signalling. We will explore this using slice electrophysiology and look at acute drug effects in naïve tissue as well as taking samples from animals at different time points after treatment. By establishing the exact nature of changes which occur over time, we anticipate being able to integrate this with the behavioural data to better explain how and why these drugs have both acute and sustained effects. Once we have established a more substantial data set, there will also be an opportunity to use more sophisticated analytical methods.