A short history of the 5-HT2C 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-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 theGPCR 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

Effects of physostigmine and scopolamine on rats' performances in object-recognition and radial-maze tests

The effects of physostigmine and scopolamine were evaluated on working memory of rats in object recognition and radial-maze tests. Three doses of physostigmine hemi-sulfate (Phys: 0.05, 0.10 and 0.20 mg/kg), five doses of scopolamine hydrobromide (Scop: 0.125, 0.25, 0.5, 1.0 and 2.0 mg/kg), and one dose of scopolamine methylbromide (Mscop: 2.0 mg/kg) were used. In object recognition test, rats were submitted to three or four intertrial delay conditions (1-min, 15-min and either 60-min or 24-h). The higher doses of Scop (1.0 and 2.0 mg/kg) in 1-min and 15-min delay and of Phys (0.20 mg/kg) in 1-min delay impaired discrimination between new and familiar objects. Mscop impaired discrimination between objects in 60-min but not in 1-min and 15-min delay. This effect may be state dependent. Radial-maze learning was impaired by the lower doses of scopolamine (0.25 and 0.50 mg/kg) which had no effect in object recognition test. These results show that in our conditions, object recognition is less sensitive than radial-maze test to cholinergic drugs