Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes

Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT 2A receptors are known for an extremely long LSD residence time, enabling minute doses to...

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Bibliographic Details
Published in:Scientific reports 2022-12, Vol.12 (1), p.21192-14, Article 21192
Main Authors: Bartuzi, Damian, Kędzierska, Ewa, Targowska-Duda, Katarzyna M., Koszła, Oliwia, Wróbel, Tomasz M., Jademyr, Simon, Karcz, Tadeusz, Szczepańska, Katarzyna, Stępnicki, Piotr, Wronikowska-Denysiuk, Olga, Biała, Grażyna, Handzlik, Jadwiga, Kristensen, Jesper L., Poso, Antti, Kaczor, Agnieszka A.
Format: Article
Language:English
Subjects:
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631/154
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Allosteric properties
Antipsychotics
Anxiety
Behavior
Coronaviruses
COVID-19
Dopamine
Drug dosages
Humanities and Social Sciences
Humans
Laboratories
Ligands
LSD
Lysergic acid diethylamide
Lysergide
Mental disorders
multidisciplinary
Pharmaceuticals
Pharmacy
Psychedelic drugs
Psychotropic drugs
Schizophrenia
Science
Science (multidisciplinary)
Serotonin
Serotonin S1 receptors
Serotonin S2 receptors
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Summary:Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT 2A receptors are known for an extremely long LSD residence time, enabling minute doses to exert a long-lasting effect. In this work, we explore the changes in anxiety-like processes induced by the previously reported antipsychotic, D2AAK1. In vivo studies revealed that the effect of D2AAK1 on the anxiety is mediated through serotonin 5-HT 1A and 5-HT 2A receptors, and that it is time-dependent (anxiogenic after 30 min, anxiolytic after 60 min) and dose-dependent. The funnel metadynamics simulations suggest complicated ligand-5HT 2A R interactions, involving an allosteric site located under the third extracellular loop, which is a possible explanation of the time-dependency. The binding of D2AAK1 at the allosteric site results in a broader opening of the extracellular receptor entry, possibly altering the binding kinetics of orthosteric ligands.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-022-25478-7