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

The status of serotonin 5-HT2A receptors (5-HT(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 5-HT2AR density. Radiotracers bind different receptor conformations depending on their agonist, antagonist or inverse agonist properties. This study investigates 5-HT2AR 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 [F-18]altanserin, the agonist [H-3]lysergic acid diethylamide (LSD) and the antagonist [H-3]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-HT2AR density was decreased when quantified by [F-18]altanserin binding, whereas increased when evaluated by [H-3]LSD binding. However, [H-3]MDL100907 binding was unaltered. A slight loss of affinity (higher K-d) was observed exclusively in [H-3]LSD binding. The findings were more evident in antipsychotic-free subjects than in antipsychotic-treated subjects. In conclusion, a higher proportion of the 5-HT2AR-active functional conformation, which is rather identified by agonist radiotracers, was observed in schizophrenia patients. A consequent reduction of the inactive 5-HT2AR 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.