title: Evidence that clozapine directly interacts on the GABAB receptor.
abstract: Neurophysiological studies suggest that clozapine may facilitate γ-aminobutyric acid (GABAergic) neurotransmission. Therefore, we studied the interaction between clozapine and the GABAB receptor (GABABR). We showed that clozapine, and not N-desmethylclozapine, which is a metabolite of clozapine, increased the binding of the GABABR antagonist, [³H]-CGP54626A, at GABABRs. Linear regression analysis showed that the correlation between the dose of clozapine and the increase of [³H]-CGP54626A binding was significant. The curve of specific [³H]-CGP54626A binding in competition with different concentrations of GABA was left shifted in the presence of clozapine. With HEK293 cells overexpressing GABABR, we showed that clozapine had a significant increase of [³H]-CGP54626A binding at GABABR1 subunit, which provided a clue of the potential therapeutic target of clozapine.
authors.affiliation: Program in Neuroscience and Mental Health, University of Toronto fCentre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Monica
authors.initials: M
authors.lastname: Blichowski
authors.forename: Zafiris J
authors.initials: ZJ
authors.lastname: Daskalakis
authors.forename: Zhouyou
authors.initials: Z
authors.lastname: Wu
authors.forename: Chun C
authors.initials: CC
authors.lastname: Liu
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Cortez
authors.forename: Orlando Carter
authors.initials: OC
authors.lastname: Snead
mesh_terms: D000818:Animals; D003024:Clozapine / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D018756:GABA Antagonists / Q000032:analysis / Q000493:pharmacokinetics*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018080:Receptors, GABA-B / Q000378:metabolism*
chemical_list: D018756:GABA Antagonists; D018080:Receptors, GABA-B; D003024:Clozapine