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Interactions of tricyclic antipsychotic and antidepressant medications with a novel binding site in GABAA receptors
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  • Konstantina Bampali,
  • Filip Koniuszewski,
  • Luca Silva,
  • Sabah Rehman,
  • Florian Vogel,
  • Thomas Seidel,
  • Petra Scholze,
  • Florian Zirpel,
  • Arthur Garon,
  • Thierry Langer,
  • Matthäus Willeit,
  • Margot Ernst
Konstantina Bampali
Medical University of Vienna

Corresponding Author:[email protected]

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Filip Koniuszewski
Medical University of Vienna
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Luca Silva
Medical University of Vienna
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Sabah Rehman
Medical University of Vienna
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Florian Vogel
Medical University of Vienna
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Thomas Seidel
University of Vienna
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Petra Scholze
Medical University of Vienna
Florian Zirpel
Medical University of Vienna
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Arthur Garon
University of Vienna
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Thierry Langer
University of Vienna
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Matthäus Willeit
Medical University of Vienna
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Margot Ernst
Medical University of Vienna
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Abstract

Background and Purpose: Many psychotherapeutic drugs including clozapine have a polypharmacological profile and act on GABAA receptors, where subtype-specific information is often lacking. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit containing GABAA receptors. Experimental Approach: Functional studies of GABA modulatory effects by antipsychotic and antidepressant medications were performed in several GABAA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Computational ligand analysis complemented the functional and mutational data. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine have negative modulatory effects on multiple GABAA receptor subtypes, including α5-containing. On the latter we show negative modulatory effects for five additional antipsychotic and antidepressant drugs. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in α5 GABAA receptor subunits. Conclusion and Implications: Our findings support previous studies suggesting a link between some of the therapeutic effects of clozapine and its negative modulatory action on certain GABAA receptor subtypes. The novel site we describe in this study is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology.
06 Apr 2021Submitted to British Journal of Pharmacology
06 Apr 2021Submission Checks Completed
06 Apr 2021Assigned to Editor
09 Apr 2021Reviewer(s) Assigned
09 May 2021Review(s) Completed, Editorial Evaluation Pending
10 May 2021Editorial Decision: Revise Minor
20 Aug 20211st Revision Received
23 Aug 2021Assigned to Editor
23 Aug 2021Submission Checks Completed
24 Aug 2021Reviewer(s) Assigned
13 Sep 2021Review(s) Completed, Editorial Evaluation Pending
14 Sep 2021Editorial Decision: Revise Minor
10 Dec 20212nd Revision Received
14 Dec 2021Submission Checks Completed
14 Dec 2021Assigned to Editor
17 Dec 2021Reviewer(s) Assigned
10 Jan 2022Review(s) Completed, Editorial Evaluation Pending
12 Jan 2022Editorial Decision: Accept