Interactions of tricyclic antipsychotic and antidepressant medications
with a novel binding site in GABAA receptors
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.