Elsevier

Neuropharmacology

Volume 38, Issue 8, August 1999, Pages 1083-1152
Neuropharmacology

Review
A review of central 5-HT receptors and their function

https://doi.org/10.1016/S0028-3908(99)00010-6Get rights and content

Abstract

It is now nearly 5 years since the last of the currently recognised 5-HT receptors was identified in terms of its cDNA sequence. Over this period, much effort has been directed towards understanding the function attributable to individual 5-HT receptors in the brain. This has been helped, in part, by the synthesis of a number of compounds that selectively interact with individual 5-HT receptor subtypes—although some 5-HT receptors still lack any selective ligands (e.g. 5-ht1E, 5-ht5A and 5-ht5B receptors). The present review provides background information for each 5-HT receptor subtype and subsequently reviews in more detail the functional responses attributed to each receptor in the brain. Clearly this latter area has moved forward in recent years and this progression is likely to continue given the level of interest associated with the actions of 5-HT. This interest is stimulated by the belief that pharmacological manipulation of the central 5-HT system will have therapeutic potential. In support of which, a number of 5-HT receptor ligands are currently utilised, or are in clinical development, to reduce the symptoms of CNS dysfunction.

Introduction

In 1986 the pharmacology of 5-hydroxytryptamine (5-HT; serotonin) was reviewed (Bradley et al.) and the existence of three 5-HT receptor families, 5-HT1–3 (comprising five receptors/binding sites in total), was acknowledged although more were suspected. At the time the function of individual 5-HT receptor subtypes in the brain was largely unclear: a 5-HT autoreceptor role was ascribed to a 5-HT1-like receptor, and it was speculated that the 5-HT2 receptor mediated a depolarising action on CNS neurones. In the 13 years since this classification, the application of molecular biological techniques has had a major impact on the 5-HT field, allowing the discovery of many additional 5-HT receptors. These are now assigned to one of seven families, 5-HT1–7, comprising a total of 14 structurally and pharmacologically distinct mammalian 5-HT receptor subtypes (for review see Hoyer et al., 1994; Fig. 1; Table 1).

Intense scrutiny has now revealed much about the functional properties of different 5-HT receptor subtypes. At the molecular level it has been established, largely using recombinant receptor models and hydropathy profiles, that the 5-HT receptor family are mostly seven putative transmembrane spanning, G-protein coupled metabotropic receptors but one member of the family, the 5-HT3 receptor, is a ligand-gated ion channel. In the intact brain the function of many 5-HT receptors can now be unequivocally associated with specific physiological responses, ranging from modulation of neuronal activity and transmitter release to behavioural change. The latter work in particular has benefitted considerably from the development of drug tools with 5-HT receptor subtype selectivity, some of which have now progressed to clinical application. Equally important, given that each receptor has a distinct and often limited distribution in the brain, has been the application of experimental approaches to evaluate receptor expression at the neuroanatomical level.

In this review we outline recent developments in the knowledge of mammalian 5-HT receptor subtypes, specifically their pharmacology, CNS distribution and actions at the molecular level. However, our main focus is the function of these receptors in the brain and, when known, in the in vivo situation. We adhere to the current classification and nomenclature of 5-HT receptor subtypes as defined by the serotonin receptor nomenclature sub-committee of IUPHAR. Some of the most recent changes in 5-HT receptor nomenclature are summarised in Table 2.

Section snippets

The 5-HT1 receptor family

The initial characterisation of the 5-HT1 receptor came from radioligand binding studies which found high affinity binding sites for [3H]-5HT in rat cortex with low affinity for spiperone (Peroutka and Snyder, 1979). Subsequent studies identified further heterogeniety within the [3H]-5-HT site, which initially accounted for the 5-HT1A and 5-HT1B receptors (Pedigo et al., 1981, Middlemiss and Fozard, 1983), and subsequently the 5-HT1C (now 5-HT2C; Pazos et al., 1984b), 5-HT1D (now recognised as

5-HT1A receptor

Following the identification of the 5-HT1A binding site (Pedigo et al., 1981, Middlemiss and Fozard, 1983) knowledge of the pharmacology and function of the receptor quickly progressed. This was driven by the early identification of a selective 5-HT1A receptor agonist, 8-OH-DPAT (Hjorth et al., 1982; but now known to also agonise 5-HT7 receptors) and the synthesis of [3H]-8-OH-DPAT and it’s application to provide the first pharmacological profile of the 5-HT1A binding site (Gozlan et al., 1983

5-HT1B receptor

The 5-HT1B receptor was initially characterised as a [3H]-5HT binding site with low affinity for spiperone in rodent brain tissue (Pedigo et al., 1981). The finding that this site had low affinity for 8-OH-DPAT established that this receptor had pharmacological properties different from the 5-HT1A (and 5-HT2) sites (Middlemiss and Fozard, 1983). Another binding site for [3H]-5HT was detected in bovine brain, and was originally classified as a 5-HT1D site on the basis of it being pharmacology

5-HT1D receptor

Using membranes prepared from bovine brain, Heuring and Peroutka (1987) detected a high affinity binding site for [3H]-5HT in the presence of ligands blocking the 5-HT1A and 5-HT1C (now 5-HT2C) binding sites, which had a pharmacology distinct from that of the 5-HT1B site detected in rodent brain. Similar sites were detected in other species including humans (Waeber et al., 1988). These findings were taken as evidence of a new 5-HT1 receptor and the binding site was given the 5-HT1D

5-ht1E receptor

The 5-ht1E receptor was first detected in radioligand binding studies which found that [3H]-5-HT, in the presence of blocking agents for other 5-HT1 subtypes that were known at that time (5-HT1A, 5-HT1B, 5-HT1C), demonstrated a biphasic displacement curve to 5-CT (Waeber et al., 1988, Leonhardt et al., 1989). The site with high affinity for 5-CT was thought to represent the 5-HT1D receptor. The low affinity site had a novel pharmacology and was seen as a novel 5-HT receptor (5-HT1E; Leonhardt

5-ht1F receptor

This 5-ht1F receptor gene was originally detected in the mouse on the basis of its sequence homology with the 5-HT1B/1D receptor subtypes (Amlaiky et al., 1992); the human gene followed shortly afterwards (Adham et al., 1993b). Initially, the receptor was designated 5-ht1Eβ (Amlaiky et al., 1992; Table 2). This was based on findings that the cloned 5-ht1F receptor had a pharmacological profile close to that of the 5-ht1E receptor (including low affinity for 5-CT) but that 5-ht1F receptor mRNA

The 5-HT2 receptor family

The 5-HT2 receptor family currently accommodates three receptor subtypes, 5-HT2A, 5-HT2B and 5-HT2C receptors, which are similar in terms of their molecular structure, pharmacology and signal transduction pathways. In recent nomenclature updates (Humphrey et al., 1993, Hoyer et al., 1994; Table 2), the 5-HT2A receptor was aligned with the 5-HT D receptor (also called 5-HT2) originally defined by Gaddum and Picarelli (1957) as mediating contractions in the guinea pig ileum. In addition, the 5-HT

5-HT2A receptor

The brain 5-HT2A receptor was initially detected in rat cortical membranes as a binding site with high affinity for [3H]-spiperone, a relatively low (micromolar) affinity for 5-HT, but with a pharmacological profile of a 5-HT receptor (Leysen et al., 1978, Peroutka and Snyder, 1979). Although this receptor was originally termed the 5-HT2 receptor (Peroutka and Snyder, 1979), it has now been attributed to the 5-HT2A receptor classification.

5-HT2B receptor

The receptor mediating the 5-HT-induced contraction of the rat stomach fundus (Vane, 1959) was originally classified as a 5-HT1-like receptor (Bradley et al., 1986). Although the receptor had pharmacological profile reminiscent of the 5-HT1C (now 5-HT2C) receptor (Buchheit et al., 1986), the rat fundus did not contain detectable amounts of 5-HT2C receptor mRNA (Baez et al., 1990). The situation was resolved by the isolation of the mouse and rat fundus receptor gene by low stringency screening

5-HT2C receptor

The 5-HT2C receptor was identified as a [3H]-5-HT binding site in choroid plexus of various species that could also be labelled by [3H]-mesulergine and [3H]-LSD but not by [3H]ketanserin (Pazos et al., 1984b). Originally this site was seen as a new member of the 5-HT1 receptor family, and termed 5-HT1C, because of its high affinity for [3H]-5-HT (Pazos et al., 1984b). However, once the receptor was cloned and more information about its characteristics became available, a shift to the 5-HT2

5-HT3 receptor

Responses mediated via the 5-HT3 receptor have been documented for over half a century, although the nomenclature has been subject to modification. For instance, it is now appreciated that Gaddum’s M receptor, responsible for indirect contraction of the guinea pig ileum, equates to the currently recognised 5-HT3 receptor.

5-HT4 receptor

The 5-HT4 receptor was initially identified in cultured mouse colliculi neurones and guinea pig brain by Bockaert and co-workers using a functional assay-stimulation of adenylate cyclase activity (Dumuis et al., 1988, Bockaert et al., 1990). Similar and additional functional responses mediated via the 5-HT4 receptor were subsequently demonstrated in various peripheral tissues (for review see Ford and Clarke, 1993). It should be noted, however, that the ability of 5-HT to stimulate adenylate

5-ht5 receptors

The 5-ht5 receptor class is probably the least well understood of all the 5-HT receptor classes. The initial cDNA sequence (designated 5-ht5A) was generated from a mouse brain library using degenerate oligonucleotides (Plassat et al., 1992a, Plassat et al., 1992b) corresponding to the regions encoding the highly conserved putative transmembrane domains III and VI of metabotropic 5-ht receptors (Hen, 1992). Subsequently, a related receptor was identified (5-ht5B) by the same group, again derived

5-ht6 receptors

The 5-ht6 receptor was initially detected by two groups following identification of a cDNA sequence which encoded a 5-HT-sensitive receptor with a novel pharmacology (Monsma et al., 1993, Ruat et al., 1993a, Ruat et al., 1993b). Both groups used the strategy of nucleotide sequence homology screening. Monsma and colleagues (1993) used highly degenerate primers derived from coding regions of the putative III and VI transmembrane domain regions of previously identified G-protein coupled receptors.

5-HT7 receptors

Notwithstanding the 5-HT7 receptor being the most recently identified 5-HT receptor, functional responses now attributed to this receptor have been documented for a number of years (for review see Eglen et al., 1997).

5-HT7 receptor cDNAs have now been identified from a number of species (e.g. Xenopus laevis (toad), mouse, rat, guinea pig, human; Bard et al., 1993, Lovenberg et al., 1993a, Lovenberg et al., 1993b, Meyerhof et al., 1993, Plassat et al., 1993, Ruat et al., 1993a, Ruat et al., 1993b

Summary and main conclusions

Since 1986, the number of recognised mammalian 5-HT receptor subtypes in the CNS has more than doubled to 14, and these have been classified into seven receptor families (5-HT1–7) on the basis of their structural, functional and to some extent pharmacological characteristics. Recent findings suggest that even this level of complexity will escalate given the existence in the brain of as yet unclassified novel 5-HT binding sites, but particularly new evidence that specific 5-HT receptor subtypes

Note added in proof

Recently, an additional 5-HT3 receptor has been identified, the human (h) 5-HT3B receptor subunit (Davies et al., 1999), would appear to be the ‘missing’ structural component of native 5-HT3 receptors. Thus, this subunit when expressed alone fails to form functional 5-HT3 receptors, although when co-expressed with the 5-HT3A receptor subunit, the resultant presumably heteromeric 5-HT3 receptor complex more fully replicates the biophysical characteristics of native neuronal 5-HT3 receptors (e.g.

Acknowledgements

The authors are grateful to colleagues and fellow scientists who contributed figures and data included in the review and for providing manuscripts prior to publication.

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