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Título

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

AutorPalacios, José M.; Pazos, Ángel ; Hoyer, Danniel
Palabras claveSertindole
Smoking cessation
Spinal cord injury
Suicide
Vabicaserin
Schizophrenia
Receptor homomers
Receptor autoradiography
RNA editing
Obesity
Mesulergine
Lorcaserin
In situ hybridization
Human brain
Heteromers
GWAS
GPCR
Drug addictions
Depression
Anxiety
Agomelatine
5-HT2C receptor
Species differences
Fecha de publicación2017
EditorSpringer Nature
CitaciónPsychopharmacology 234(9-10): 1395-1418 (2017)
ResumenThis paper is a personal account on the discovery and characterization of the 5-HT receptor (first known as the 5-HT receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HTR, the 5-HTR was discovered while studying the pharmacological features and the distribution of [H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [H]mesulergine-labelling to the rat choroid plexus. [H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT binding, the new binding site was called 5-HT because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HTR (later named 5-HT) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HTR is a GPCR, with a very complex gene structure. It constitutes a rarity in the GPCR family: many 5-HTR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HTR splice variants. Intense research led to therapeutically active 5-HT receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5-HTR antagonists/inverse agonists. Agomelatine, a 5-HTR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HTR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HTR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HTR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HTR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HTR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HTR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain.
Versión del editorhttps://doi.org/10.1007/s00213-017-4545-5
URIhttp://hdl.handle.net/10261/164691
Identificadoresdoi: 10.1007/s00213-017-4545-5
e-issn: 1432-2072
issn: 0033-3158
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