Neuronal 5-HT Receptors and SERT Nicholas M. Barnes1 and John F. Neumaier2 1Cellular and Molecular Neuropharmacology Research Group, Section of Neuropharmacology and Neurobiology, Clinical and Experimental Medicine, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT UK and 2Department of Psychiatry, University of Washington, Seattle, WA 98104 USA. Correspondence: [email protected] and [email protected] Nicholas Barnes is Professor of Neuropharmacology at the University of Birmingham Medical School, and focuses on serotonin receptors and the serotonin transporter. John Neumaier is Professor of Psychiatry and Behavioural Sciences and Director of the Division of Neurosciences at the University of Washington. His research concerns the role of serotonin receptors in emotional behavior. Contents Introduction Introduction ........................................................................ 1 5-hydroxytryptamine (5-HT, serotonin) is an ancient biochemical manipulated through evolution to be DRIVING RESEARCH FURTHER The 5-HT1 Receptor Family ............................................... 1 utilized extensively throughout the animal and plant kingdoms. Mammals employ 5-HT as a 5-HT Receptors ............................................................ 2 1A neurotransmitter within the central and peripheral nervous systems, and also as a local hormone in 5-HT Receptors ............................................................ 2 1B numerous other tissues, including the gastrointestinal tract, the cardiovascular system and immune cells. 5-HT Receptors ............................................................ 3 1D This multiplicity of function implicates 5-HT in a vast array of physiological and pathological processes. 5-ht Receptors .............................................................. 3 1e This plethora of roles has consequently encouraged 5-HT Receptors ............................................................ 3 the development of many compounds of therapeutic 1F value, including various antidepressant, antipsychotic and antiemetic drugs. The 5-HT2 Receptor Family ............................................... 4 Part of the ability of 5-HT to mediate a wide range 5-HT2A Receptors ............................................................ 4 of actions arises from the imposing number of 5- HT receptors.1 Numerous 5-HT receptor families 5-HT Receptors ............................................................ 5 2B and subtypes have evolved. Currently, 18 genes are recognized as being responsible for 14 distinct 5-HT Receptors ............................................................ 5 2C mammalian 5-HT receptor subtypes, which are divided into 7 families, all but one of which are The 5-HT Receptor ........................................................... 5 3 members of the G-protein coupled receptor (GPCR) superfamily. The exception is the 5-HT receptor, The 5-HT Receptor ........................................................... 7 3 4 a Cys-loop ligand-gated ion channel (LGIC) that in evolutionary terms arose independent of the GPCR The 5-ht5 Receptors ........................................................... 8 5-HT receptors along with other members of this superfamily (e.g. the nicotinic acetylcholine receptor, The 5-HT6 Receptors ......................................................... 9 2+ GABAA receptor, glycine receptor and the Zn - The 5-HT7 Receptor ......................................................... 10 activated receptor). Further receptor heterogeneity is generated through alternative splicing (e.g. 5-HT3, The 5-HT Transporter (SERT) ......................................... 10 5-HT4 and 5-HT7 receptors), RNA editing (the 5-HT2C receptor), and the putative formation of homo- and 2 Conclusion ....................................................................... 11 heterodimers (5-HT4 and the β2 adrenoceptor). References ....................................................................... 12 The 5-HT1 Receptor Family This family consists of five separate gene products: 5-HT Receptor Compounds ............................................ 13 5-HT1A, 5-HT1B, 5-HT1D, 5-ht1e, and 5-HT1F receptors. Tocris Bioscience Scientific Review Series Tocris Bioscience Scientific Review Series Previously, some of these were thought to be species- ligands include some of the atypical antipsychotics, specific homologs (e.g. 5-HT1B receptor in rats and which have partial agonist or neutral antagonist 5-HT1D receptor in humans), but the genes for each activity and buspirone, a partial agonist that is used of these receptors are now known to be present in for generalized anxiety disorder. 5-HT1A receptor every mammalian species examined so far. Each is partial agonists are clinically useful anxiolytic encoded by a single, intron-less reading frame and drugs and may act on the autoreceptors to reduce they share considerable sequence homology. All serotonergic activity, whereas 5-HT1A receptors of these receptors couple to Gi/o to inhibit adenylyl in the hippocampus have been implicated in the cyclase and reduce cAMP levels, but additional signal mechanism of antidepressant action (by facilitating transduction mechanisms have also been described. neurogenesis) and in regulating the hypothalamic- While their gene structure and molecular properties pituitary-adrenal axis. Other physiological effects of are similar, important cellular differences and distinct CNS 5-HT1A receptor activation include hypothermia, 1 patterns of regional expression in the body underlie hyperphagia, and serotonin syndrome. 5-HT1A divergent physiological features. Several of these receptor knockout mice have heightened anxiety and receptors are well known as autoreceptors that may exhibit diminished depression-like features.4,5 As regulate the excitability of serotonin neurons and the with the other serotonin receptors this may involve release of serotonin,3 but also they are expressed receptor actions during early brain development as in nonserotonergic neurons, where they can have well as during processing of emotional experience analogous effects on other neurotransmitters. in the adult. A number of highly selective ligands for 5-HT receptors have been developed, although it 5-HT Receptors 1A 1A should also be noted that some of these share affinity 5-HT1A receptors are distributed broadly in the CNS, for 5-HT7 receptors (e.g. 8-OH-DPAT) and others found in the soma, dendrites and in some cases for other 5-HT or 5-HT receptors. WAY 100635 the axon hillock of neurons, and the cell body and 1 2 has often been used as a highly selective 5-HT1A processes of astrocytes. This receptor is expressed receptor neutral antagonist. Xaliproden and S-14506 by all serotonin neurons (as autoreceptors) and by are selective agonists. many nonserotonergic neurons (as heteroreceptors). The electrophysiological effect of 5-HT1A receptor 5-HT1B Receptors activation on neurons is generally inhibitory and 5-HT1B receptors are also distributed broadly in the acts by reducing neuronal firing rate. A number of CNS in serotonergic and nonserotonergic neurons; highly selective ligands have been developed, and these receptors are predominantly translocated to they range from full agonists to partial agonists, axon terminals, so there is an anatomical mismatch antagonists, and inverse agonists. 5-HT1A receptors between the localization of mRNA and mature 5-HT1B are thought to be therapeutic targets for several receptor protein. Historically the 5-HT1B receptor was neuropsychiatric disorders including anxiety, thought to be the rat analog of 5-HT1D receptors, but depression, and schizophrenia. Clinically used it is now clear that both receptors are present in all mammalian species examined and their regional distributions differ.6 β-adrenergic antagonists have high affinity for 5-HT receptors in some but not all Figure 1A | 5-HT1A subtype-selective compounds 1B species. 5-HT1B autoreceptors have been found to O reduce 5-HT synthesis and release and enhance H OH reuptake via the serotonin transporter. 5-HT N 1B N heteroreceptors inhibit the release of a range of N H O N N different neurotransmitters, depending on the neuron N types that express them. Systemic administration of 5-HT receptor agonists have several behavioral 8-Hydroxy-DPAT (0529) Tandospirone (2854) 1B effects including increased locomotion, changes 5-HT1A agonist 5-HT1A partial agonist in brain reward mechanisms, and decreased aggression, whereas selective antagonists may have F O 7,8 H some procognitive potential. The expression of O tBu OMe N N H these receptors in diverse and potentially competing N N sets of neurons may impact their utility as a clinical target, although several 5-HT1B/D receptor agonists are H2N O effective as antimigraine treatments. 5-HT1B receptor knockout mice have been tested extensively and NAD 299 (3282) (S)-WAY 100135 (1253) have a distinct phenotype characterized by increased 5-HT1A antagonist 5-HT1A antagonist aggression and, in most cases, predisposition for addiction-like behaviors. Their phenotype may | Neuronal 5-HT Receptors however depend on compensatory changes in the 5-ht1e Receptors dopamine system during development rather than The lower case letters denote that this receptor has being due to decreased 5-HT1B receptor signaling in not been confirmed to have meaningful physiological adults. Several moderately selective agonists have functions in vivo. The existence of this receptor been developed, including CP 93129 and