Evidence that clozapine directly interacts on the GABAB receptor

Neurophysiological studies suggest that clozapine may facilitate gamma-aminobutyric acid (GABAergic) neurotransmission. Therefore, we studied the interaction between clozapine and the GABA(B) receptor (GABA(B)R). We showed that clozapine, and not N-desmethylclozapine, which is a metabolite of clozapine, increased the binding of the GABA(B)R antagonist, [H-3]-CGP54626A, at GABA(B)Rs. Linear regression analysis showed that the correlation between the dose of clozapine and the increase of [H-3]-CGP54626A binding was significant. The curve of specific [H-3]-CGP54626A binding in competition with different concentrations of GABA was left shifted in the presence of clozapine. With HEK293 cells overexpressing GABA(B)R, we showed that clozapine had a significant increase of [H-3]-CGP54626A binding at GABA(B)R1 subunit, which provided a clue of the potential therapeutic target of clozapine. NeuroReport 22:637-641 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.