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

Review

DOI: 10.1007/s00213-017-4545-5

Cite this article as:
Palacios, J.M., Pazos, A. & Hoyer, D. Psychopharmacology (2017). doi:10.1007/s00213-017-4545-5

Abstract

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5-HT1C 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-HT2C receptor 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-HT2 binding, the new binding site was called 5-HT1C because 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-HT2C receptor 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.

Keywords

5-HT2C receptor GPCR GWAS Receptor autoradiography In situ hybridization Species differences Human brain RNA editing Receptor homomers Heteromers Depression Anxiety Obesity Smoking cessation Spinal cord injury Drug addictions Schizophrenia Suicide Mesulergine Agomelatine Lorcaserin Vabicaserin Sertindole 

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Jose M. Palacios
    • 1
  • Angel Pazos
    • 2
  • Daniel Hoyer
    • 3
    • 4
    • 5
  1. 1.Frontera Biotechnology SLBarcelonaSpain
  2. 2.Instituto de Biomedicina y Biotecnología de Cantabria, IBBTECUniversidad de Cantabria, CSIC, SODERCAN, Centro de Investigación Biomédica en Red de Salud Mental CIBERSAMSantanderSpain
  3. 3.Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health SciencesThe University of MelbourneParkvilleAustralia
  4. 4.The Florey Institute of Neuroscience and Mental HealthThe University of MelbourneParkvilleAustralia
  5. 5.Department of Molecular MedicineThe Scripps Research InstituteLa JollaUSA