title: A short history of the 5-HT2Creceptor: from the choroid plexus to depression, obesity and addiction treatment.
abstract: This paper is a personal account on the discovery and characterization of the 5-HT2Creceptor (first known as the 5-HT1Creceptor) 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-HT2Creceptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]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 [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2binding, the new binding site was called 5-HT1Cbecause of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5-HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in the GPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2Creceptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5-HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR 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-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR 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-HT2CR 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-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain.
authors.affiliation: Frontera Biotechnology SL, 08013, Barcelona, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Palacios
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC, Universidad de Cantabria, CSIC, SODERCAN, Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Santander, 39011, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Pazos
authors.affiliation: Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia. d.hoyer@unimelb.edu.au.|The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia. d.hoyer@unimelb.edu.au.|Department of Molecular Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA, 92037, USA. d.hoyer@unimelb.edu.au.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoyer
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000378:metabolism; D016739:Behavior, Addictive / Q000188:drug therapy / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002831:Choroid Plexus / Q000187:drug effects / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism*; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000008:administration & dosage / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000008:administration & dosage / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists
keywords: 5-HT2C receptor; Agomelatine; Anxiety; Depression; Drug addictions; GPCR; GWAS; Heteromers; Human brain; In situ hybridization; Lorcaserin; Mesulergine; Obesity; RNA editing; Receptor autoradiography; Receptor homomers; Schizophrenia; Sertindole; Smoking cessation; Species differences; Spinal cord injury; Suicide; Vabicaserin