Opposite Alterations of 5¬HT2A Receptor Brain Density in Subjects with Schizophrenia: Relevance of Radiotracers Pharmacological Profile
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Date
2021-05-20Author
García Bea, Aintzane
Gómez Vallejo, Vanessa
Martín Muñoz, Abraham
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Translational Psychiatry 11 : (2021) // Article ID 302
Abstract
The status of serotonin 5HT2A receptors (5HT2ARs) in schizophrenia has been controversial. In vivo positron emission
tomography neuroimaging and in vitro post-mortem binding studies have reported conflicting results about 5HT2AR
density. Radiotracers bind different receptor conformations depending on their agonist, antagonist or inverse agonist
properties. This study investigates 5HT2AR 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 [18F]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 (Bmax)
and the affinity of the respective radiotracers (Kd). In schizophrenia subjects, 5-HT2AR density was decreased when
quantified by [18F]altanserin binding, whereas increased when evaluated by [3
H]LSD binding. However, [3
H]
MDL100907 binding was unaltered. A slight loss of affinity (higher Kd) 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-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-HT2ARs in schizophrenia.