The Multiplicity of Serotonin Receptors: Uselessly Diverse Molecules or an Embarrassment of Riches?

A large number of 5-HT receptors (>15) have been identified by molecular cloning technology over the past 10 years. This review briefly summarizes available information regarding the functional and therapeutic implications of serotonin receptor diversity for neurology and psychiatry. 5-HT receptors are divided into seven main families: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. Several families (e.g., 5-HT1 family) have many members (e.g., 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F), each of which is encoded by a distinct gene product. In addition to the genomic diversity of 5-HT receptors, splice variants and editing isoforms exist for many of the 5-HT receptors, making the family even more diverse. Evidence that is summarized in this review suggests that 5-HT receptors represent novel therapeutic targets for a number of neurologic and psychiatric diseases including migraine headaches, chronic pain conditions, schizophrenia, anxiety, depression, eating disorders, obsessive compulsive disorder, pervasive developmental disorders, and obesity-related conditions (Type II diabetes, hypertension, obesity syndromes). It is possible that sub-type-selective serotonergic agents may revolutionize the treatment for a number of medical, psychiatric, and neurological disorders.

[1]  D. Woolley,et al.  A BIOCHEMICAL AND PHARMACOLOGICAL SUGGESTION ABOUT CERTAIN MENTAL DISORDERS. , 1954, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Gershon,et al.  Clozapine--a potential antipsychotic agent without extrapyramidal manifestations. , 1974, Current therapeutic research, clinical and experimental.

[3]  Richard J. Miller,et al.  Anti-muscarinic properties of neuroleptics and drug-induced Parkinsonism , 1974, Nature.

[4]  H. L. Goldberg,et al.  The comparative efficacy of buspirone and diazepam in the treatment of anxiety. , 1979, The American journal of psychiatry.

[5]  S H Snyder,et al.  Multiple serotonin receptors: differential binding of [3H]5-hydroxytryptamine, [3H]lysergic acid diethylamide and [3H]spiroperidol. , 1979, Molecular pharmacology.

[6]  J. Palacios,et al.  The binding of serotonergic ligands to the porcine choroid plexus: characterization of a new type of serotonin recognition site. , 1984, European journal of pharmacology.

[7]  R. Glennon,et al.  Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. , 1984, Life sciences.

[8]  H. Meltzer,et al.  Differential Effect of Subchronic Treatment with Various Neuroleptic Agents on Serotonin2 Receptors in Rat Cerebral Cortex , 1986, Journal of neurochemistry.

[9]  B. Cohen,et al.  In vivo potencies of antipsychotic drugs in blocking alpha 1 noradrenergic and dopamine D2 receptors: implications for drug mechanisms of action. , 1986, Life sciences.

[10]  M. Cohen,et al.  Contractile serotonergic receptor in rat stomach fundus. , 1987, The Journal of pharmacology and experimental therapeutics.

[11]  B. Roth,et al.  Multiple mechanisms of serotonergic signal transduction. , 1987, Life sciences.

[12]  A. Doenicke,et al.  POSSIBLE BENEFIT OF GR43175, A NOVEL 5-HT1-LIKE RECEPTOR AGONIST, FOR THE ACUTE TREATMENT OF SEVERE MIGRAINE , 1988, The Lancet.

[13]  M. Caron,et al.  The genomic clone G-21 which resembles a β-adrenergic receptor sequence encodes the 5-HT1A receptor , 1988, Nature.

[14]  G. Aghajanian,et al.  Potency of antipsychotics in reversing the effects of a hallucinogenic drug on locus coeruleus neurons correlates with 5-HT2 binding affinity. , 1988, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[15]  E. sanders-Bush,et al.  Lysergic acid diethylamide and 2,5-dimethoxy-4-methylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis. , 1988, The Journal of pharmacology and experimental therapeutics.

[16]  S. Peroutka,et al.  Sumatriptan (GR 43175) interacts selectively with 5-HT1B and 5-HT1D binding sites. , 1989, European journal of pharmacology.

[17]  H. Meltzer,et al.  Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. , 1989, The Journal of pharmacology and experimental therapeutics.

[18]  M. Titeler,et al.  Detection of a Novel Serotonin Receptor Subtype (5‐HT1E) in Human Brain: Interaction with a GTP‐Binding Protein , 1989, Journal of neurochemistry.

[19]  G. Kennett,et al.  Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT1C receptor antagonists. , 1989, European journal of pharmacology.

[20]  J. Bockaert,et al.  BRL 24924: a potent agonist at a non-classical 5-HT receptor positively coupled with adenylate cyclase in colliculi neurons. , 1989, European journal of pharmacology.

[21]  T. Jessell,et al.  The 5HT2 receptor defines a family of structurally distinct but functionally conserved serotonin receptors. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[22]  B. Wells,et al.  Buspirone in the Treatment of Posttraumatic Stress Disorder , 1991, Pharmacotherapy.

[23]  R. Myers,et al.  Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. , 1991, Science.

[24]  J. Amsterdam,et al.  Buspirone in major depression: a controlled study. , 1991, The Journal of clinical psychiatry.

[25]  B. Roth,et al.  Binding of typical and atypical antipsychotic agents to transiently expressed 5-HT1C receptors. , 1992, The Journal of pharmacology and experimental therapeutics.

[26]  R. McGuffin,et al.  Molecular cloning and functional characterization of a human 5-HT1B serotonin receptor: a homologue of the rat 5-HT1B receptor with 5-HT1D-like pharmacological specificity. , 1992, Biochemical and biophysical research communications.

[27]  T. Branchek,et al.  Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT1D alpha and 5-HT1D beta. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[28]  B. Roth,et al.  Identification of receptor domains that modify ligand binding to 5-hydroxytryptamine2 and 5-hydroxytryptamine1c serotonin receptors. , 1992, Molecular pharmacology.

[29]  L L Iversen,et al.  Molecular cloning of a serotonin receptor from human brain (5HT1E): a fifth 5HT1-like subtype. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[30]  S. Woods,et al.  Anger and anxiety responses to m-chlorophenylpiperazine in generalized anxiety disorder , 1992, Biological Psychiatry.

[31]  M. Erlander,et al.  A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms , 1993, Neuron.

[32]  J. Kehne,et al.  Characterization of the 5-HT2 receptor antagonist MDL 100907 as a putative atypical antipsychotic: behavioral, electrophysiological and neurochemical studies. , 1993, The Journal of pharmacology and experimental therapeutics.

[33]  D. Murphy,et al.  A comparison of the behavioral effects of oral versus intravenous mCPP administration in OCD patients and the effect of metergoline prior to IV mCPP , 1993, Biological Psychiatry.

[34]  S. Woods,et al.  m-Chlorophenylpiperazine effects in neuroleptic-free schizophrenic patients. Evidence implicating serotonergic systems in the positive symptoms of schizophrenia. , 1993, Archives of general psychiatry.

[35]  D. Sibley,et al.  Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. , 1993, Molecular pharmacology.

[36]  M. Mattei,et al.  Mouse 5-hydroxytryptamine5A and 5-hydroxytryptamine5B receptors define a new family of serotonin receptors: cloning, functional expression, and chromosomal localization. , 1993, Molecular pharmacology.

[37]  D. Sibley,et al.  Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype. , 1993, The Journal of biological chemistry.

[38]  Antagonists of 5-HT4 receptor-mediated responses in adult hippocampal neurons. , 1994, The Journal of pharmacology and experimental therapeutics.

[39]  D. Sibley,et al.  Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors. , 1994, The Journal of pharmacology and experimental therapeutics.

[40]  D. Nelson,et al.  Molecular cloning, functional expression, and mRNA tissue distribution of the human 5-hydroxytryptamine2B receptor. , 1994, Molecular pharmacology.

[41]  R Hen,et al.  Enhanced aggressive behavior in mice lacking 5-HT1B receptor. , 1994, Science.

[42]  I. Forbes,et al.  In vivo properties of SB 200646A, a 5‐HT2C/2B receptor antagonist , 1994, British journal of pharmacology.

[43]  R. Hen,et al.  Regulation of [3H]5-HT release in raphe, frontal cortex and hippocampus of 5-HT1B knock-out mice , 1995, Neuroreport.

[44]  David Julius,et al.  Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors , 1995, Nature.

[45]  G. Baxter,et al.  Mediation by 5‐hydroxytryptamine2B receptors of endothelium‐dependent relaxation in rat jugular vein , 1995, British journal of pharmacology.

[46]  P R Saxena,et al.  Serotonin receptors: subtypes, functional responses and therapeutic relevance. , 1995, Pharmacology & therapeutics.

[47]  G. Martin,et al.  Classification and nomenclature of 5-HT receptors: a comment on current issues , 1995, Behavioural Brain Research.

[48]  D. Sibley,et al.  Localization of serotonin subtype 6 receptor messenger RNA in the rat brain by in situ hybridization histochemistry , 1995, Neuroscience.

[49]  S. Yamawaki,et al.  Chronic antidepressant exposure enhances 5-hydroxytryptamine7 receptor-mediated cyclic adenosine monophosphate accumulation in rat frontocortical astrocytes. , 1996, Journal of Pharmacology and Experimental Therapeutics.

[50]  P. Blier,et al.  Sequential administration of augmentation strategies in treatment‐resistant obsessive‐compulsive disorder: preliminary findings , 1996, International clinical psychopharmacology.

[51]  D. Sibley,et al.  Cloning, Characterization, and Chromosomal Localization of a Human 5‐HT6 Serotonin Receptor , 1996, Journal of neurochemistry.

[52]  C. Montigny,et al.  Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists , 1996, Trends in Neurosciences.

[53]  T. Branchek,et al.  A receptor autoradiographic and in situ hybridization analysis of the distribution of the 5‐ht7 receptor in rat brain , 1996, British journal of pharmacology.

[54]  S. Garattini,et al.  Pharmacology of ingestive behaviour. , 1996, The´rapie (Paris).

[55]  P. Séguéla,et al.  Differential expression of sumatriptan-sensitive 5-hydroxytryptamine receptors in human trigeminal ganglia and cerebral blood vessels. , 1996, Molecular pharmacology.

[56]  J. Halford,et al.  The 5-HT2 Receptor Agonist MK-212 Reduces Food Intake and Increases Resting but Prevents the Behavioural Satiety Sequence , 1997, Pharmacology Biochemistry and Behavior.

[57]  R. Emeson,et al.  Regulation of serotonin-2C receptor G-protein coupling by RNA editing , 1997, Nature.

[58]  R. Eglen,et al.  RS-102221: A Novel High Affinity and Selective, 5-HT2C Receptor Antagonist , 1997, Neuropharmacology.

[59]  D. Middlemiss,et al.  Effects of selective h5-HT1B (SB-216641) and h5-HT1D (BRL-15572) receptor ligands on guinea-pig and human 5-HT auto- and heteroreceptors , 1997, Naunyn-Schmiedeberg's Archives of Pharmacology.

[60]  M. Rapport The Discovery of Serotonin , 2015, Perspectives in biology and medicine.

[61]  Kirk W. Johnson,et al.  5‐HT1F receptor agonists inhibit neurogenic dural inflammation in guinea pigs , 1997, Neuroreport.

[62]  A. Brown,et al.  SB 242084, a Selective and Brain Penetrant 5-HT2C Receptor Antagonist , 1997, Neuropharmacology.

[63]  R. Hen,et al.  5-Hydroxytryptamine1B receptors modulate the effect of cocaine on c-fos expression: converging evidence using 5-hydroxytryptamine1B knockout mice and the 5-hydroxytryptamine1B/1D antagonist GR127935. , 1997, Molecular pharmacology.

[64]  T. Branchek,et al.  Characterization of LY344864 as a pharmacological tool to study 5-HT1F receptors: binding affinities, brain penetration and activity in the neurogenic dural inflammation model of migraine. , 1997, Life sciences.

[65]  A. Sleight,et al.  The 5-hydroxytryptamine6 receptor-selective radioligand [3H]Ro 63-0563 labels 5-hydroxytryptamine receptor binding sites in rat and porcine striatum. , 1998, Molecular pharmacology.

[66]  J. Bockaert,et al.  5‐HT4 Receptors: Gene, Transduction and Effects on Olfactory Memory , 1998, Annals of the New York Academy of Sciences.

[67]  M. Jurzak,et al.  The human 5-ht5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells. , 1998, European journal of pharmacology.

[68]  D. Middlemiss,et al.  SB‐224289–a novel selective (human) 5‐HT1B receptor antagonist with negative intrinsic activity , 1998, British journal of pharmacology.

[69]  L. Tecott,et al.  Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene , 1998, Nature Medicine.

[70]  W. Kroeze,et al.  The molecular biology of serotonin receptors: therapeutic implications for the interface of mood and psychosis , 1998, Biological Psychiatry.

[71]  A. Sleight,et al.  Involvement of 5‐HT6 receptors in nigro‐striatal function in rodents , 1998, British journal of pharmacology.

[72]  R. Hen,et al.  Putative 5‐ht5 Receptors: Localization in the Mouse CNS and Lack of Effect in the Inhibition of Dural Protein Extravasation , 1998, Annals of the New York Academy of Sciences.

[73]  L. Phebus,et al.  Serotonin in migraine: theories, animal models and emerging therapies. , 1998, Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques.

[74]  A. Sleight,et al.  5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential. , 1998, The Journal of pharmacology and experimental therapeutics.

[75]  R. Hen,et al.  Absence of Fenfluramine-Induced Anorexia and Reduced c-fos Induction in the Hypothalamus and Central Amygdaloid Complex of Serotonin 1B Receptor Knock-Out Mice , 1998, The Journal of Neuroscience.

[76]  R. Emeson,et al.  Identification and Characterization of RNA Editing Events within the 5‐HT2C Receptor a , 1998, Annals of the New York Academy of Sciences.

[77]  R. Hen,et al.  Locomotor response to MDMA is attenuated in knockout mice lacking the 5-HT1B receptor , 1999, Psychopharmacology.

[78]  P. Pauwels,et al.  F 11356, a novel 5-hydroxytryptamine (5-HT) derivative with potent, selective, and unique high intrinsic activity at 5-HT1B/1D receptors in models relevant to migraine. , 1999, The Journal of pharmacology and experimental therapeutics.

[79]  John A. Peters,et al.  The 5-HT3B subunit is a major determinant of serotonin-receptor function , 1999, Nature.

[80]  M. Geyer,et al.  Increased Exploratory Activity and Altered Response to LSD in Mice Lacking the 5-HT5A Receptor , 1999, Neuron.

[81]  A. Anand,et al.  The use of pindolol with fluoxetine in the treatment of major depression: final results from a double-blind, placebo-controlled trial , 1999, Biological Psychiatry.

[82]  L. Tecott,et al.  Reduced satiating effect of d-fenfluramine in serotonin 5-HT2C receptor mutant mice , 1999, Psychopharmacology.

[83]  Colleen M. Niswender,et al.  RNA Editing of the Human Serotonin 5-Hydroxytryptamine 2C Receptor Silences Constitutive Activity* , 1999, The Journal of Biological Chemistry.

[84]  B. Roth,et al.  Activation is Hallucinogenic and Antagonism is Therapeutic: Role of 5-HT2A Receptors in Atypical Antipsychotic Drug Actions , 1999 .

[85]  J. Bockaert,et al.  Novel brain-specific 5-HT4 receptor splice variants show marked constitutive activity: role of the C-terminal intracellular domain. , 1999, Molecular pharmacology.

[86]  Johnson Gw,et al.  Present and future of 5-HT receptor agonists as antimigraine drugs. , 1999 .

[87]  R. Emeson,et al.  Serotonin-2C Receptor Pre-mRNA Editing in Rat Brain andin Vitro by Splice Site Variants of the Interferon-inducible Double-stranded RNA-specific Adenosine Deaminase ADAR1* , 1999, The Journal of Biological Chemistry.

[88]  T. Svensson,et al.  Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by alpha2 adrenoceptor blockade. , 1999, Science.

[89]  T. Dawson,et al.  Regulation of alternative splicing by RNA editing , 1999, Nature.

[90]  P. Pauwels,et al.  Present and future of 5-HT receptor agonists as antimigraine drugs. , 1999, Clinical neuropharmacology.