Serotonin 5-HT 2A receptors in schizophrenia: Reflexions on an unfinished story

For decades, the dopaminergic hypothesis has dominated the study of schizophrenia, focusing on striatal dopamine D2 receptors as the primary drivers of positive symptoms. However, as the limitations of this model become clearer, researchers are increasingly looking toward the serotonergic system—specifically the 5-HT2A receptor (5-HT2AR)—as a critical component of the disease's pathophysiology. While classical psychedelics, which act as 5-HT2AR agonists, mimic certain psychotic symptoms, the role of these receptors in the clinical manifestation of schizophrenia has remained frustratingly elusive and controversial.

A primary source of confusion in the field is the discrepancy between clinical studies. Post-mortem brain studies often report increased 5-HT2AR density, while positron emission tomography (PET) imaging studies in living subjects frequently report the opposite. The authors argue that this is not due to flawed data, but rather to the inherent molecular nature of G protein-coupled receptors (GPCRs). These receptors oscillate between inactive and active, G-protein-coupled conformations.

Because different radiotracers possess different binding properties—some acting as agonists, others as inverse agonists—they essentially "see" different populations of the receptor. Agonist tracers bind preferentially to the active state, while inverse agonists bind to the inactive state. Therefore, if schizophrenia involves a shift in the equilibrium toward the active, G-protein-coupled conformation, studies using different types of tracers will naturally yield contradictory results regarding receptor density.

This paper suggests that the previously observed inconsistencies are reconcilable under the ternary complex model. By acknowledging that 5-HT2ARs exist in an interchangeable equilibrium, researchers can interpret the "decreased" density found by inverse agonist tracers alongside the "increased" density found by agonist tracers as evidence of an upregulation of the functionally active receptor state. The authors call for future PET studies that compare multiple radiotracer types within the same subjects to definitively map this serotonergic imbalance. Confirming this shift could be vital for developing more precise psychiatric treatments that target specific receptor states rather than simply blocking total receptor density.