Evaluación del receptor de serotonina 5-HT2A en esquizofrenia: un ejemplo de investigación traslacional basada en farmacología

Alterations of the functional status of brain serotonin 5-HT2A receptors play a key role in schizophrenia symptoms. In vivo positron emission tomography neuroimaging and in vitro postmortem studies have reported conflicting results on 5-HT2A receptors in schizophrenia. The apparent discrepancies could be explained in the context of the ternary complex model of ligand-receptor-G protein interaction. Schizophrenia shows an imbalance towards the active receptor conformation of 5-HT2A, which explains the different results obtained between agonist and inverse agonist radiotracer drugs. In schizophrenia, 5-HT2A receptor activation by agonists displays a selective funcional hyperactivity for the signaling pathway involving Gi/o-proteins. The activation of this pathway is considered a fingerprint of hallucinogenic properties. In contrast, the 5-HT2A receptor canonical signaling pathway, which involves Gq/11 activation, is not altered. Through the use inverse agonists, it was demonstrated an increased constitutive activity of 5-HT2A receptors in brain cortex of schizophrenia subjects, that exclusively affects the Gi/o-protein-mediated signaling pathway. According to these findings, the optimal antipsychotic activity would be represented by a biased inverse agonism on the pro-hallucinogenic pathway of 5-HT2A receptors, leaving the canonical signaling pathway unaltered.