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

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.

Psychedelic drugs generate a unique emotional state in humans, but we know little about the underlying molecular, cellular and neural mechanisms involved. Emerging evidence suggest that psychedelics are an example of a novel class of small molecule which induce plasticity changes in specific neural circuits. These so called, psychoplastogens generate both immediate and sustained effects on mood which we now propose involve both psychological and neuroplastic effects. We have recently established that drugs which are considered as psychoplastogens share a common ability to modulate affective biases. Affective biases describe the effects of emotions on cognition and are a neuropsychological mechanism contributing to both normal and pathological emotional states. This project will investigate the effects of psychedelic drugs on these affective biases. We have already shown that a key receptor target for psychedelics, the 5-HT2A agonist, is able to directly modulate these affective biases. The planned studies bring together behavioural studies, using our translational affective bias test, with slice electrophysiology and in vivo oxygen amperometry. We will explore the mechanisms which underlie serotonergic modulation, particularly 5-HT1A and 5-HT2A receptors, of this important neuropsychological mechanism. Our research will focus on two psychedelic drugs, the direct agonist, psilocybin and the indirect agonist, MDMA. Through combining behavioural studies with systemic pharmacology, targeted brain infusions and studies with selective inhibitors we will explore both their immediate and sustained effects. Integrating the behavioural work with in vitro and ex vivo slice electrophysiology with enable us to better understand the underlying molecular and cellular mechanisms which mediate their behavioural effects. Using oxygen amperometry will start to explore the neural circuits modulating affective biases and their interaction with psychedelics.