Serotonin and brain function : a tale of two receptors

RL Carhart-Harris and DJ Nutt

Abstract

Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important – and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.

Keywords : Depression, serotonin, psychedelics

Introduction

Overview

The aim of this paper is to discuss the function of brain serotonin (5-HT) transmission by focusing on two of its major receptor sub- types, the 5-HT1AR and 5-HT2AR. Our selective focus on these receptors is justified by their dense and widespread expression in the human brain (Beliveau et al., 2016), diametrically opposite functional effects (Araneda and Andrade, 1991) and extensive evidence implicating both in psychiatric disorders and their treat- ment (Chattopadhyay, 2007). We believe that a fuller understand- ing of the function of 5-HT1A and particularly, 5-HT2A receptor signalling motivates a revision of current thinking on a well- known problem in neuropsychopharmacology, namely: what principal function is served by brain serotonin transmission? Broadly consistent with prior theories (Deakin, 2013), we main- tain that a key function of brain 5-HT is to moderate anxiety and stress, and promote patience and coping (Miyazaki et al., 2012) via (postsynaptic) 5-HT1AR signalling. Crucially however, we also extend on this by proposing that a second major function of brain 5-HT is to open a window of plasticity for greater adaptation (Branchi, 2011), mediated in large part by 5-HT2AR signalling. This bipartite model is consistent with a ‘flexible coping’ model of brain serotonin function, in which postsynaptic 5-HT1ARs mediate so-called ‘passive coping’ (i.e. tolerating but not neces- sarily dealing with a source of psychological pain) and 5-HT2ARs mediate ‘active coping’ (actively dealing with a source of psycho- logical pain by changing one’s relationship to it) (Puglisi-Allegra and Andolina, 2015). Note: we use the term ‘plasticity’ in a broad sense throughout this paper to refer to the capacity for change and we address our intentional neglect of the other serotonin receptors in the discussion section as well as immediately below.

The charge that our neglect of the functioning of the full range of serotonin receptors means that the present paper cannot be considered a fully comprehensive model of brain serotonin func- tion is one we accept. However, we propose that the functioning of signalling at other serotonin receptors (than 1A and 2A) may, in several cases, be comfortably incorporated into either (or both) arms of the bipartite model we introduce below – and we encour- age attempts to do this. A final introductory caveat is that signal- ling at serotonin receptors can have more than one function, depending on such factors as: basal serotonin efflux and related synaptic concentrations, the specific localisation of the relevant receptor subtype (e.g. whether they are pre- or postsynaptic), the temporal development or time course of a specific pharmacological manipulation, and the animal’s present behavioural state (e.g. see Mitchell, 2005 for a relevant review). As much as is possible, we have endeavoured to acknowledge such inherent complexities in the serotonin system – particularly when we feel they are criti- cal for a proper comprehension of the relevant phenomenon – but this has had to be balanced against considerations of parsimony and focus – in any already extensive narrative review.

With these caveats entered, let us return to the main focus of this paper: brain serotonin functioning – as seen through postsyn- aptic 5-HT1A and 5-HT2A receptor signalling. The 5-HT1AR is highly expressed in brain regions involved in regulating stress and emotion and 5-HT has an especially high affinity for its 1A receptor (Peroutka and Snyder, 1979). We suggest that the 5-HT1AR and its associated functions dominate 5-HT transmis- sion under normal conditions but that 5-HT2AR signalling also serves a role that becomes increasingly important during extreme states when 5-HT release is elevated. We propose that 5-HT mediates stress moderation and plasticity-mediated adaptability in response to different levels of stress and adversity, via its post- synaptic 1A and 2A receptors respectively. We acknowledge that agonism at other 5-HT receptors has also been linked with neuro- trophic factors and other molecular markers of neuroplasticity (Kraus et al., 2017); however, our focus here is on the remarkable psychological and functional plasticity associated with the acute ‘psychedelic’ state – as produced by psychedelic drugs such as LSD and psilocybin (Carhart-Harris et al., 2016c) – and the enduring changes that appear to follow from exposure to these drugs’ effects (e.g. MacLean et al., 2011). We also propose that combined signalling at the 5-HT1A and 2A receptors has a gener- ally complementary influence on mood, facilitating stress relief (5-HT1AR-mediated) but also a flexibility of mind (5-HT2AR- mediated) that under favourable conditions (Alboni et al., 2017; Branchi, 2011; Chiarotti et al., 2017; Hartogsohn, 2016), is con- ducive to positive mood (Hirt et al., 2008; Schmid et al., 2015). In what follows, we present evidence supporting these hypothe- ses and discuss their clinical significance.

The function of brain serotonin is an enigma

There have been several attempts to identify a unifying function of dopaminergic transmission in the brain (Berridge and Robinson, 1998; Schultz, 2010; Schwartenbeck et al., 2014) and similar attempts have been made for serotonin (Andrews et al., 2015; Azmitia, 2007; Branchi, 2011; Dayan and Huys, 2009; Deakin, 1998). Most researchers acknowledge that the function of the 5-HT system remains ‘elusive’ (Dayan and Huys, 2009) and ‘a puzzle’ (Cools et al., 2008; Dayan and Huys, 2015; Seymour et al., 2012) and it is argued here that this may be due to the spe- cial diversity and complexity of the serotonin system with its many receptor subtypes (Hoyer et al., 1994), extensive innerva- tion of the brain and paracrine style of transmission (Hornung, 2003; Jennings, 2013). The notion that 5-HT is an enigma among neuromodulators (said to be ‘involved in everything but responsi- ble for nothing’ (Muller and Homberg, 2015)) is relevant here, and it is argued that the riddle of 5-HT can only be solved by focusing on its individual receptor subtypes.

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