Opposite alterations of 5HT2A receptor brain density in subjects with schizophrenia: relevance of radiotracers pharmacological profile

Serotonin 5-HT2A receptor density in the prefrontal cortex of people with schizophrenia depends on which radiotracer is used to measure it, because different tracers bind different receptor conformations. Using the inverse agonist [18F]altanserin, receptor density appeared decreased; using the agonist [3H]LSD, it appeared increased; and using the antagonist [3H]MDL100907, it was unchanged. These differences were more pronounced in schizophrenia subjects who were antipsychotic-free at death. The findings suggest a shift toward the active functional conformation of the 5-HT2A receptor in schizophrenia, consistent with increased cortical serotonin 2A receptor activity.

Study at a glance

Abstract

Abstract The status of serotonin 5­HT 2A receptors (5­HT 2A Rs) in schizophrenia has been controversial. In vivo positron emission tomography neuroimaging and in vitro post-mortem binding studies have reported conflicting results about 5­HT 2A R density. Radiotracers bind different receptor conformations depending on their agonist, antagonist or inverse agonist properties. This study investigates 5­HT 2A R density in the post-mortem prefrontal cortex from subjects with schizophrenia and controls using three radiotracers with a different pharmacological profile. The specific binding parameters of the inverse agonist [ 18 F]altanserin, the agonist [ 3 H]lysergic acid diethylamide (LSD) and the antagonist [ 3 H]MDL100907 to brain cortex membranes from 20 subjects with schizophrenia and 20 individually matched controls were evaluated under similar methodological conditions. Ten schizophrenia subjects were antipsychotic-free at death. Saturation curve analyses were performed by non-linear regression to obtain a maximal density of binding sites ( B max ) and the affinity of the respective radiotracers ( K d ). In schizophrenia subjects, 5-HT 2A R density was decreased when quantified by [ 18 F]altanserin binding, whereas increased when evaluated by [ 3 H]LSD binding. However, [ 3 H]MDL100907 binding was unaltered. A slight loss of affinity (higher K d ) was observed exclusively in [ 3 H]LSD binding. The findings were more evident in antipsychotic-free subjects than in antipsychotic-treated subjects. In conclusion, a higher proportion of the 5-HT 2A R-active functional conformation, which is rather identified by agonist radiotracers, was observed in schizophrenia patients. A consequent reduction of the inactive 5-HT 2A R conformation, which is preferentially identified by inverse agonist radiotracers, was also obtained. Antagonist radiotracers do not distinguish between molecular conformations of the receptor, and accordingly, the absence of changes was shown. These results are compatible with the proposed increased functional activity of brain cortical 5-HT 2A Rs in schizophrenia.