Central 5-HT receptors and their function; present and future

Highlights

• Highlights developments in non-canonical 5-HT receptor signalling, and biased agonism.

• Reviews 5-HT receptor mapping and cellular distribution.

• Highlights pharmacological tools for 5-HT receptor manipulation.

• Reviews behavioural and cognitive effects of 5-HT receptor manipulation.

• Highlights progression of 5-HT ligands from preclinical to clinical investigation.

Abstract

Since our review of central 5-HT receptors and their function twenty years ago, no new 5-HT receptor has been discovered and there is little evidence that this situation will change in the near future. Nevertheless, over this time significant progress has been made in our understanding of the properties of these receptors and in the clinical translation of this information, and some of these developments are highlighted herein. Such highlights include extensive mapping of 5-HT receptors in both animal and human brain, culminating in readily-accessible brain atlases of 5-HT receptor distribution, as well as emerging data on how 5-HT receptors are distributed within complex neural circuits. Also, a range of important pharmacological and genetic tools have been developed that allow selective 5-HT receptor manipulation, in cells through to whole organism models. Moreover, unexpected complexity in 5-HT receptor function has been identified including agonist-dependent signalling that goes beyond the pharmacology of canonical 5-HT receptor signalling pathways set down in the 1980s and 1990s. This new knowledge of 5-HT signalling has been extended by the discovery of combined signalling of 5-HT and co-released neurotransmitters, especially glutamate. Another important advance has been the progression of a large number of 5-HT ligands through to experimental medicine studies and clinical trials, and some such agents have already become prescribed therapeutic drugs. Much more needs to be discovered and understood by 5-HT neuropharmacologists, not least how the diverse signalling effects of so many 5-HT receptor types interact with complex neural circuits to generate neurophysiological changes which ultimately lead to altered cognitions and behaviour.

This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.

Introduction

Following the initial identification of two types of 5-HT receptor in peripheral tissue sixty years ago, termed ‘D’ and ‘M’ 5-HT receptors (Gaddum and Picarelli, 1957), a combination of pharmacological and then molecular biological investigations led to the discovery of an unexpected diversity of 5-HT receptor types. An excellent account of the history of 5-HT receptor discovery and classification is given by Bockaert and colleagues (Bockaert et al., 2010). The current consensus is that the brain expresses 7 types of 5-HT receptors (5-HT_1-7) comprising a total of 14 subtypes (Fig. 1), although 2 of these receptors, 5-ht_1e and 5-ht_5b, retain lower case appellation and are still classed as gene products since they have not yet been linked to a functional response in native cells/tissues. All 5-HT receptor subtypes are found in both brain and peripheral tissues with the exception of 5-ht_1e, 5-HT_2C and 5-HT₆ receptors, for which there is limited expression outside the CNS. Also, multiple isoforms of certain 5-HT receptors (notably 5-HT_2C, 5-HT₃, 5-HT₄ and 5-HT₇ receptors) have been reported, but the pharmacological and functional significance of this diversity remains uncertain. This receptor diversity is comparable to that of the most complex neurotransmitter systems including those of glutamate and purines. Despite this complexity, a wide range of selective agonists, antagonists and radioligands are now available to target specific 5-HT receptor subtypes (summarized in Table 1) and probe their localisation, signalling properties, and CNS function.

In the human genome, the 5-HT receptor subtypes are coded by 17 genes, with 12 encoding metabotropic 5-HT receptors and 5 encoding subunits for ionotropic 5-HT₃ receptors (an additional sequence in the human genome corresponds to the 5-ht_5b receptor in some other species, although the presence of stop codons in the human gene prevents full length protein expression). The genes encoding 5-HT receptors (and the 5-HT transporter) demonstrate numerous polymorphisms in coding and non-coding regions, which are often common in the human population. It is clear from animal studies that changes in 5-HT receptor expression are associated with clear-cut changes in behaviour (O'Leary et al., 2020; see later). Moreover, there are many reports of associations between specific 5-HT receptor gene polymorphisms (and other 5-HT genes) and particular psychiatric disorders or drug therapy effects, as detailed in recent excellent reviews (O'Leary et al., 2020; McGowan and Reynolds, 2020). However, as with the vast majority of such candidate gene-associations, effect sizes are often modest and findings typically require confirmation in genome-wide association studies. To illustrate the importance of replication in large scale datasets, in a recent example 18 candidate genes for depression, including the 5-HT transporter, 5-HT_2A receptor and tryptophan hydroxylase, failed to replicate in large population-based and case-control samples (~62,000–440,000 samples) even when taking into account environmental interactions (Border et al., 2019). This area of 5-HT research is now expanding to incorporate new findings of epigenetic regulation of 5-HT genes (Albert et al., 2019; Friedel and Heinz, 2020) which might help better understand how natural variation in 5-HT receptor expression links to vulnerability to CNS disorder. Consequently, the importance of variability in 5-HT receptor genes as mental health risk factors currently remains uncertain, and further detailed analysis and review is warranted.