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

Eletrococleografia extratimpânica na neuropatia/dessincronia auditiva Extratympanic electrocochleography in the diagnosis of auditory neuropathy/auditory dyssynchrony

O potencial evocado auditivo de tronco encefálico (PEATE) vem sendo amplamente utilizado como método para avaliação da função coclear em indivíduos com diagnóstico de neuropatia/dessincronia auditiva (NA/DA). Na ausência das emissões otoacústicas, muitos casos de NA/DA foram diagnosticados pela presença do microfonismo coclear (MC) identificado no PEATE. OBJETIVO: Demonstrar a aplicabilidade clínica da eletrococleografia extratimpânica (Ecog-ET) no diagnóstico diferencial da NA/DA quando comparada ao PEATE. MATERIAL E MÉTODO: Uma criança com 4 anos de idade, com diagnóstico de NA/DA atendida no Centro de Pesquisas Audiológicas realizou a Ecog-ET com tone burst de 2000Hz nas polaridades de rarefação e condensação. RESULTADOS: Ilustrou-se o registro da Ecog-ET. Com a utilização de protocolo apropriado, o MC pode ser evidenciado e confirmado na Ecog, com qualidade de registro superior ao obtido no PEATE. CONCLUSÃO: A Ecog-ET permitiu uma análise mais detalhada do MC quando comparada ao PEATE tendo, portanto aplicabilidade clínica na investigação da função coclear na NA/DA.<br>The brainstem auditory evoked potential (BAEP) is being extensively used as a method for the evaluation of cochlear function in individuals with diagnosis of auditory neuropathy/auditory dyssynchrony (AN/AD). In the absence of otoacoustic emissions, many cases of AN/AD have been diagnosed by the presence of CM identified in the BAEP. AIM: to demonstrate the clinical applicability of extratympanic electrocochleography (ET-Ecochg) in the differential diagnosis of AN/AD compared to the BAEP. METHOD: a 4-year-old child with a diagnosis of AN/AD seen at the Audiological Research Center was submitted to ET-Ecochg with a 2000 Hz tone burst in rarefaction and condensation polarities. RESULTS: the ET-Ecochg exam was illustrated. Using an appropriate protocol, it was possible to demonstrate CM and to confirm it in the Ecochg, with a recording quality superior to that obtained in the BAEP. CONCLUSION: ET-Ecochg permitted a more detailed analysis of CM compared to the BAEP, thus showing clinical applicability for the investigation of cochlear function in AN/AD