Opposite alterations of 5HT2A receptor brain density in subjects with schizophrenia: relevance of radiotracers pharmacological profile
This post-mortem study (n=22) quantified the binding density of serotonin 5HT2A receptors in deceased patients with schizophrenia and found that the active configuration of this receptor, as measured by a two-fold higher agonistic binding of LSD radioligand, had the highest density amongst schizophrenic patients who were not being treated with antipsychotic medication.
Authors
- Diez-Alarcia, R.
- Muguruza, C.
- Rivero, G.
Published
Abstract
Introduction
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.
Methods
The specific binding parameters of the inverse agonist [18F]altanserin, the agonist [3H]lysergic acid diethylamide (LSD) and the antagonist [3H]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).
Results
In schizophrenia subjects, 5-HT2AR density was decreased when quantified by [18F]altanserin binding, whereas increased when evaluated by [3H]LSD binding. However, [3H]MDL100907 binding was unaltered. A slight loss of affinity (higher Kd) was observed exclusively in [3H]LSD binding. The findings were more evident in antipsychotic-free subjects than in antipsychotic-treated subjects.
Discussion
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.
Research Summary of 'Opposite alterations of 5HT2A receptor brain density in subjects with schizophrenia: relevance of radiotracers pharmacological profile'
Introduction
Diez-Alarcia and colleagues frame their study within longstanding but inconsistent evidence about serotonin 5-HT2A receptors (5-HT2ARs) in schizophrenia. Earlier in vivo PET studies and in vitro post-mortem binding work have reported decreases, increases or no change in cortical 5-HT2AR density. The authors note that much of this variation may relate not only to clinical and demographic heterogeneity or antipsychotic exposure, but also to the pharmacological profiles of radiotracers: agonists preferentially label the G-protein-coupled high-affinity (functionally active) receptor state, inverse agonists prefer the uncoupled low-affinity (inactive) state, while neutral antagonists bind both states with similar affinity. This mechanistic distinction has received relatively little attention when comparing prior studies. The present study therefore aims to test whether opposing alterations in 5-HT2AR density in schizophrenia depend on the intrinsic activity of the radioligand used. To do so, the investigators performed head-to-head saturation binding assays on membrane homogenates from the same post-mortem dorsolateral prefrontal cortex samples, using three radiotracers with distinct pharmacology: the agonist [3H]LSD, the antagonist [3H]MDL100907, and the inverse agonist [18F]altanserin. The objective was to determine whether agonist, antagonist and inverse agonist radioligands yield different estimates of receptor density (Bmax) and affinity (Kd) in subjects with schizophrenia compared with matched controls, and whether antipsychotic exposure at death affects those measures.
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Study Details
- Study Typeindividual
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- APA Citation
Diez-Alarcia, R., Muguruza, C., Rivero, G., García-Bea, A., Gómez-Vallejo, V., Callado, L. F., Llop, J., Martín, A., & Meana, J. J. (2021). Opposite alterations of 5HT2A receptor brain density in subjects with schizophrenia: relevance of radiotracers pharmacological profile. Translational Psychiatry, 11(1). https://doi.org/10.1038/s41398-021-01430-7
References (2)
Papers cited by this study that are also in Blossom
Geyer, M. A., Vollenweider, F. X. · Trends in Pharmacological Sciences (2008)
González-Maeso, J., Sealfon, S. C. · Trends in Neuroscience (2009)
Cited By (1)
Papers in Blossom that reference this study
Dourron, H. M., Strauss, C., Hendricks, P. S. · Pharmacological Reviews (2022)
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