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

This 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.