Neuropharmacology 38 (1999) 1083–1152 www.elsevier.com/locate/neuropharm Review A review of central 5-HT receptors and their function Nicholas M. Barnes a,*, Trevor Sharp b,1 a Department of Pharmacology, The Medical School, Uni6ersity of Birmingham, Edgbaston, Birmingham B15 2TT, UK b Uni6ersity Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford OX26HE, UK Accepted 21 January 1999 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. © 1999 Published by Elsevier Science Ltd. All rights reserved. Keywords: Serotonin; 5-hydroxytryptamine; 5-HT receptor function Contents 1. Introduction ...................................................................... 1085 2. The 5-HT1 receptor family.............................................................. 1086 3. 5-HT1A receptor.................................................................... 1086 3.1. 5-HT1A receptor structure.......................................................... 1087 3.2. 5-HT1A receptor distribution ........................................................ 1087 3.3. 5-HT1A receptor pharmacology ...................................................... 1088 3.4. Functional effects mediated via the 5-HT1A receptor .......................................... 1089 3.4.1. Second messenger responses................................................... 1089 3.4.2. Electrophysiological responses ................................................. 1089 3.4.2.1. Hippocampus and other forebrain regions .................................... 1089 3.4.2.2. Dorsal raphe nucleus ................................................ 1089 3.5. 5-HT release ................................................................. 1091 3.6. Acetylcholine release............................................................. 1091 3.7. Noradrenaline release ............................................................ 1091 3.7.1. Behavioural and other physiological responses ........................................ 1091 4. 5-HT1B receptor .................................................................... 1092 4.1. 5-HT1B receptor structure.......................................................... 1093 4.2. 5-HT1B receptor distribution ........................................................ 1093 * Corresponding author. Tel.: +44-121-4144499; fax: +44-121-4144509. E-mail addresses: [email protected] (N.M. Barnes), [email protected] (T. Sharp) 1 Trevor Sharp, Tel: +44-1865-224690. 0028-3908/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved. PII: S0028-3908(99)00010-6 1084 N.M. Barnes, T. Sharp / Neuropharmacology 38 (1999) 1083–1152 4.3. 5-HT1B receptor pharmacology.......................................................1094 4.4. Functional effects mediated via the 5-HT1B receptor ..........................................1094 4.4.1. Second messenger responses...................................................1094 4.4.2. 5-HT1B autoreceptors ......................................................1094 4.4.3. 5-HT1B heteroreceptors .....................................................1095 4.4.4. Behavioural and other physiological responses ........................................1096 5. 5-HT1D receptor....................................................................1097 5.1. 5-HT1D receptor structure .........................................................1097 5.2. 5-HT1D receptor distribution ........................................................1097 5.3. 5-HT1D receptor pharmacology ......................................................1098 5.4. Functional effects mediated via the 5-HT1D receptor ..........................................1098 5.4.1. Second messenger responses...................................................1098 5.4.2. 5-HT1D autoreceptors ......................................................1098 5.4.3. 5-HT1D heteroreceptors .....................................................1099 5.4.4. Behavioural and other physiological responses ........................................1099 6. 5-ht1E receptor.....................................................................1099 6.1. 5-ht1E receptor structure ..........................................................1099 6.2. 5-ht1E receptor distribution .........................................................1099 6.3. 5-ht1E receptor pharmacology .......................................................1100 6.4. Functional effects mediated via the 5-ht1E receptor ...........................................1100 7. 5-ht1F receptor.....................................................................1100 7.1. 5-ht1F receptor structure ..........................................................1100 7.2. 5-ht1F receptor distribution .........................................................1100 7.3. 5-ht1F receptor pharmacology .......................................................1101 7.4. Functional effects mediated via the 5-ht1F receptor ...........................................1101 8. The 5-HT2 receptor family..............................................................1101 9. 5-HT2A receptor....................................................................1102 9.1. 5-HT2A receptor structure..........................................................1102 9.2. 5-HT2A receptor distribution ........................................................1102 9.3. 5-HT2A receptor pharmacology ......................................................1104 9.4. Functional effects mediated via the 5-HT2A receptor ..........................................1104 9.4.1. Second messenger responses...................................................1104 9.4.2. Electrophysiological responses .................................................1105 9.4.3. Behavioural and other physiological responses ........................................1105 10. 5-HT2B receptor ....................................................................1106 10.1. 5-HT2B receptor structure..........................................................1106 10.2. 5-HT2B receptor distribution ........................................................1106 10.3. 5-HT2B receptor pharmacology.......................................................1107 10.4. Functional effects mediated via the 5-HT2B receptor ..........................................1107 10.4.1. Signal transduction........................................................1107 10.4.2. Behavioural responses ......................................................1107 11. 5-HT2C receptor ....................................................................1107 11.1. 5-HT2C receptor structure..........................................................1107 11.2. 5-HT2C receptor distribution ........................................................1108 11.3. 5-HT2C receptor pharmacology ......................................................1108 11.4. Functional effects mediated via the 5-HT2C receptor ..........................................1108 11.4.1. Signal transduction........................................................1108 11.4.2. Electrophysiological responses .................................................1109 11.4.3. Behavioural and other physiological responses ........................................1109 12. 5-HT3 receptor ....................................................................1110 12.1. 5-HT3 receptor structure ..........................................................1110 12.2. 5-HT3 receptor distribution .........................................................1111 12.3. 5-HT3 receptor pharmacology .......................................................1112 12.4. Are there additional 5-HT3 receptor subunits? ..............................................1112 12.5. Functional effects mediated via the 5-HT3 receptor ...........................................1114 12.6. Functional actions of the 5-HT3 receptor relevant to anxiety .....................................1114 12.7. Functional actions of the 5-HT3 receptor relevant to cognition ....................................1115 12.8. Association of the 5-HT3 receptor with dopamine function in the brain ...............................1117 13. 5-HT4 receptor ....................................................................1118 13.1. 5-HT4 receptor structure ..........................................................1118 13.2. 5-HT4 receptor distribution .........................................................1120