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

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.

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Neuropharmacology 38 (1999) 1083–1152
Review
A review of central 5-HT receptors and their function
Nicholas M. Barnesa,*, Trevor Sharpb,1
aDepartment of Pharmacology, The Medical School, Uni?ersity of Birmingham, Edgbaston, Birmingham B15 2TT, UK
bUni?ersity Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford OX2 6HE, 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-ht5Aand 5-ht5Breceptors). 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-HT1receptor family. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
3. 5-HT1Areceptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
3.1.5-HT1Areceptor structure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1087
3.2.5-HT1Areceptor distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1087
3.3.5-HT1Areceptor pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1088
3.4.Functional effects mediated via the 5-HT1Areceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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-HT1Breceptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1092
4.1.5-HT1Breceptor structure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093
4.2.5-HT1Breceptor distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093
www.elsevier.com/locate/neuropharm
* Corresponding author. Tel.: +44-121-4144499; fax: +44-121-4144509.
E-mail addresses: n.m.barnes@bham.ac.uk (N.M. Barnes), trevor.sharp@clinpharm.ox.ac.uk (T. Sharp)
1Trevor 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

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N.M. Barnes, T. Sharp / Neuropharmacology 38 (1999) 1083–11521084
4.3.
4.4.
5-HT1Breceptor pharmacology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094
Functional effects mediated via the 5-HT1Breceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094
4.4.1. Second messenger responses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094
4.4.2.5-HT1Bautoreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094
4.4.3.5-HT1Bheteroreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095
4.4.4. Behavioural and other physiological responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1096
5. 5-HT1Dreceptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097
5.1. 5-HT1Dreceptor structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097
5.2. 5-HT1Dreceptor distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097
5.3. 5-HT1Dreceptor pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1098
5.4. Functional effects mediated via the 5-HT1Dreceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1098
5.4.1. Second messenger responses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1098
5.4.2. 5-HT1Dautoreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1098
5.4.3. 5-HT1Dheteroreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
5.4.4.Behavioural and other physiological responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
6. 5-ht1Ereceptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
6.1. 5-ht1Ereceptor structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
6.2.5-ht1Ereceptor distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
6.3.5-ht1Ereceptor pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1100
6.4.Functional effects mediated via the 5-ht1Ereceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1100
7. 5-ht1Freceptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1100
7.1.5-ht1Freceptor structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1100
7.2.5-ht1Freceptor distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1100
7.3.5-ht1Freceptor pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101
7.4.Functional effects mediated via the 5-ht1Freceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101
8. The 5-HT2receptor family. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101
9. 5-HT2Areceptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1102
9.1.5-HT2Areceptor structure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1102
9.2.5-HT2Areceptor distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1102
9.3.5-HT2Areceptor pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1104
9.4.Functional effects mediated via the 5-HT2Areceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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-HT2Breceptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106
10.1.5-HT2Breceptor structure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106
10.2.5-HT2Breceptor distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106
10.3.5-HT2Breceptor pharmacology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
10.4.Functional effects mediated via the 5-HT2Breceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
10.4.1.Signal transduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
10.4.2.Behavioural responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
11. 5-HT2Creceptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
11.1.5-HT2Creceptor structure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
11.2.5-HT2Creceptor distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108
11.3.5-HT2Creceptor pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108
11.4.Functional effects mediated via the 5-HT2Creceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108
11.4.1.Signal transduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108
11.4.2.Electrophysiological responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109
11.4.3.Behavioural and other physiological responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109
12. 5-HT3receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1110
12.1.5-HT3receptor structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1110
12.2.5-HT3receptor distribution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111
12.3.5-HT3receptor pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112
12.4.Are there additional 5-HT3receptor subunits?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112
12.5.Functional effects mediated via the 5-HT3receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1114
12.6.Functional actions of the 5-HT3receptor relevant to anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1114
12.7.Functional actions of the 5-HT3receptor relevant to cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115
12.8.Association of the 5-HT3receptor with dopamine function in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1117
13. 5-HT4receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1118
13.1.5-HT4receptor structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1118
13.2.5-HT4receptor distribution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120

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13.3.
13.4.
5-HT4receptor pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120
Functional effects mediated via the 5-HT4receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120
13.4.1. Transduction system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120
13.4.2.Modulation of neurotransmitter release following interaction with the 5-HT4receptor. . . . . . . . . . . . . . . . . 1120
13.4.3.Modulation of behaviour via interaction with the 5-HT4receptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1122
Cognitive performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1122
Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1124
14. 5-ht5receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125
14.1.5-ht5Areceptor structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125
14.2. 5-ht5Breceptor structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125
14.3. Genomic structure of 5-ht5Aand 5-ht5Breceptor genes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1126
14.4.5-ht5Areceptor distribution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1126
14.5.5-ht5Breceptor distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1126
14.6. 5-ht5receptor ontogeny . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1126
14.7. 5-ht5receptor pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1127
14.8.Functional effects mediated via the 5-ht5receptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1127
15. 5-ht6receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1128
15.1.5-ht6receptor structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1128
15.2.5-ht6receptor distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1128
15.3.5-ht6receptor pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1129
15.4. Functional effects mediated via the 5-HT6receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131
15.5.Behavioural consequences following interaction with the 5-ht6receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131
16. 5-HT7receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1132
16.1.5-HT7receptor structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1132
16.2.5-HT7receptor distribution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133
16.3.5-HT7receptor pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133
16.4.Functional responses mediated via the 5-HT7receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133
16.4.1.Transduction system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133
16.4.2.Circadian rhythms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133
16.4.3.Modulation of neuronal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133
16.4.4.Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1134
16.4.5.Manipulation of receptor expression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1134
17. Summary and main conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1134
18. Note added in proof . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1135
19. Unlinked list. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1136
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1136
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1136
13.5.
13.6.
1. 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(com-
prisingfivereceptors/bindingsitesintotal),wasacknowl-
edged 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-HT2receptor 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, compris-
ing 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 sub-
types. At the molecular level it has been established,
largely using recombinant receptor models and hy-
dropathy profiles, that the 5-HT receptor family are
mostly seven putative transmembrane spanning, G-
protein coupled metabotropic receptors but one mem-
ber of the family, the 5-HT3receptor, 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 dis-
tinct and often limited distribution in the brain, has
been the application of experimental approaches to

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N.M. Barnes, T. Sharp / Neuropharmacology 38 (1999) 1083–11521086
evaluate receptor expression at the neuroanatomical
level.
In this review we outline recent developments in the
knowledge of mammalian 5-HT receptor subtypes, spe-
cifically their pharmacology, CNS distribution and ac-
tions 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 recep-
tor 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.
2. The 5-HT1receptor family
The initial characterisation of the 5-HT1receptor
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 heterogeni-
ety within the [3H]-5-HT site, which initially accounted
for the 5-HT1Aand 5-HT1Breceptors (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 a combination of the species variant
of the 5-HT1Breceptor and the closely related 5-HT1D
receptor; Hoyer et al., 1985a,b; Heuring and Peroutka,
1987), 5-ht1E(Leonhardt et al., 1989) and 5-ht1F(Am-
laiky et al., 1992; Adham et al., 1993a,b) receptors. A
high affinity binding site for [3H]-5-HT with novel
5-HT1-likepharmacology has recently been detected in
mammalian brain (Castro et al., 1997b) but has yet to
be sufficently characterised for inclusion in the 5-HT1
receptor family. The receptors of the 5-HT1family have
high amino acid sequence homology (Table 1; Fig. 1)
and all couple negatively to adenylate cyclase via G-
proteins.
The general pharmacological characteristics of the
5-HT1receptors was initially set out in 1986 by Bradley
et al. (e.g. effects mimicked by 5-CT, blocked/mimicked
by methiothepin/methysergide and not blocked by se-
lective antagonists of the 5-HT2and 5-HT3receptors).
Recently this classification has been revised to take into
account several factors, specifically the unusual proper-
ties of the 5-ht1Eand 5-ht1Freceptors (low affinity for
5-CT and methiothepin), the move of the 5-HT1Crecep-
tor to the 5-HT2receptor family (5-HT2Creceptor), and
the discoveryofadditional
(Humphrey et al., 1993; Hoyer et al., 1994). The most
recent development is a realignment of 5-HT1Band
5-HT1Dnomenclature (Hartig et al., 1996; see later).
(5-HT4–7)receptors
3. 5-HT1Areceptor
Following the identification of the 5-HT1Abinding
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-HT1Areceptor ago-
nist, 8-OH-DPAT (Hjorth et al., 1982; but now known
to also agonise 5-HT7receptors) and the synthesis of
[3H]-8-OH-DPAT and it’s application to provide the
first pharmacological profile of the 5-HT1Abinding site
(Gozlan et al., 1983). These initial breakthroughs, to-
gether with the discovery that buspirone and a series of
Fig. 1. Dendrogram showing the evolutionary relationship between
various human 5-HT receptor protein sequences (except 5-HT5Aand
5-HT5Breceptors which are murine in origin), created using programs
from the GCG package (Genetics Computer Group Inc). Multiple
sequence alignments were created using a simplification of the pro-
gressive alignment method of Feng and Doolittle (1987). A distance
matrix was created from the pairwise evolutionary distances between
aligned sequences, expressed as substitutions per 100 amino acids. A
phylogenetic tree was constructed from this distance matrix using the
unweighted pair group method with arithmetic averages. 5-HT1A
receptor (Kobilka et al., 1987), 5-HT1Breceptor (Demchyshyn et al.,
1992), 5-HT1Dreceptor (Hamblin and Metcalf, 1991), 5-ht1E(Zgom-
bick et al., 1992), 5-ht1Freceptor (Adham et al., 1993a,b), 5-HT2A
receptor (Cook et al., 1994), 5-HT2Breceptor (Schmuck et al., 1994),
5-HT2Creceptor (Xie et al., 1996), 5-HT3As(Hope et al., 1993),
5-HT4receptor van den Wyngaert et al., 1997), 5-HT5Areceptor
(Plassat et al., 1992a,b), 5-ht5Breceptor (Matthes et al., 1993), 5-ht6
receptor (Kohen et al., 1996), 5-HT7receptor (Bard et al., 1993).

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N.M. Barnes, T. Sharp / Neuropharmacology 38 (1999) 1083–11521087
Table 1
Comparison of the percentage amino acid identity between the different human 5-HT receptor subtypesa
1B1D1A 1E1F2A2B 2C3As4 5A 5B67
1A
1B
1D
1E
1F
2A
2B
2C
3As
4
5A
5B
6
7
100
43
43
40
42
31
35
32
?10%b
29
35
38
34
38
100
63
48
49
31
27
28
?10%b
32
35
34
31
37
100
48
49
29
27
30
?10%b
31
36
34
32
38
100
57
34
30
32
?10%b
31
36
34
32
39
100
32
29
33
?10%b
34
37
35
32
38
100
45
51
?10%b
28
25
27
28
28
100
42
?10%b
28
26
29
27
28
100
?10%b
28
28
29
27
28
100
?10%b
?10%b
?10%b
?10%b
?10%b
100
33
29
27
32
100
69
30
32
100
32
34
100
33100
aThe percentages were created using the algorithm of Needleman and Wunsch (1970) to find the alignment of two complete sequences that
maximises the number of matches and minimises the number of gaps (GCG package, Genetics Computer Group, Inc.). Sequences as for Fig. 1.
bDue to the low percent amino acid identity, the program was unable to align the 5-HT3Asreceptor with the other 5-HT receptor sequences.
structurally related 5-HT1Aligands were anxiolytic and
antidepressant in the clinic (Traber and Glaser, 1987;
Robinson et al., 1990), go a long way towards explain-
ing why the 5-HT1Areceptor is the best characterised of
the 5-HT receptors discovered to date.
3.1. 5-HT1Areceptor structure
The 5-HT1Areceptor was the first 5-HT receptor to
be fully sequenced. Both the human and rat 5-HT1A
receptors were identified by screening a genomic library
for homologous sequences to the ?2-adrenoceptor (Ko-
bilka et al., 1987; Fargin et al., 1988; Albert et al.,
1990). Experiments on mutated forms of the receptor
have established that a single amino acid residue in the
7th transmembrane domain (Asn 385) confers the high
affinity of the receptor for certain ?-adrenoceptor lig-
ands (Guan et al., 1992).
The rat 5-HT1Areceptor (422 amino acids) has 89%
homology with the human receptor, and the gene is
intronless with a tertiary structure typical of a seven
transmembrane spanning protein with sites for glycosy-
lation and phosphorylation. The human receptor is
localised on chromosome 5 (5q11.2–q13).
3.2. 5-HT1Areceptor distribution
The distribution of the 5-HT1Areceptor in brain has
been mapped extensively by receptor autoradiography
using a range of ligands including [3H]-5-HT, [3H]-8-
OH-DPAT, [3H]-ipsapirone, [125I]-BH-8-MeO-N-PAT
andmorerecently,[125I]-p-MPPI
100635(PazosandPalacios,
Nanopoulus et al., 1985; Hoyer et al., 1986; Verge et
al., 1986; Radja et al., 1991; Khawaja, 1995; Kung et
and[3H]-WAY
Weissmann-1985;
al., 1995). The latter ligand has also been used for the
in vivo labelling of 5-HT1Areceptors in mouse brain
(Laporte et al., 1994). Recently, PET studies have used
[11C]-WAY 100635 to image 5-HT1Areceptors in the
living human brain (Pike et al., 1995).
The density of 5-HT1Abinding sites is high in limbic
brain areas, notably hippocampus, lateral septum, cor-
tical areas (particularly cingulate and entorhinal cor-
tex), and also the mesencephalic raphe nuclei (both
dorsal and median raphe nuclei). In contrast, levels of
5-HT1Abinding sites in the basal ganglia and cerebel-
lum are barely detectable.
The distribution of mRNA encoding the 5-HT1A
receptor is almost identical to that of the 5-HT1A
binding site (Chalmers and Watson, 1991; Miquel et al.,
1991; Pompeiano et al., 1992; Burnet et al., 1995). The
overall pattern of 5-HT1Areceptor distribution is simi-
Table 2
Summary of recent important changes in 5-HT receptor nomencla-
ture
Old nomenclatureNew nomenclature
ReceptorSpecies
Rat
Human, guinea pig
All species
5-HT1B
5-HT1D
5-HT1D?
5-HT1Ba
5-HT1D?
All species5-HT1D
5-HT2
5-HT D
All species5-HT2A
5-HT2F
5-HT1C
All species
All species
5-HT2B
5-HT2C
aSpecies equivalent, e.g. r5-HT1Bfor rodents and h5-HT1Bfor
humans.