GABA(A) receptor subtype selectivity underlying anxiolytic effect of 6-hydroxyflavone.

6-Hydroxyflavone (6HF), a naturally occurring flavonoid, was previously reported to bind to type A gamma-aminobutyric acid (GABA(A)) receptors benzodiazepine (BZ) site with moderate binding affinity. In the present study, we showed that 6HF partially potentiated GABA-induced currents in native GABA(A) receptors expressed in cortical neurons via BZ site, as the enhancement was blocked by the antagonist flumazenil. Furthermore, in patch clamp studies, 6HF displayed significant preference for alpha(2)- and alpha(3)-containing subtypes, which were thought to mediate anxiolytic effect, compared to alpha(1)- and alpha(5)-containing subtypes expressed in HEK 293T cells. In mice, 6HF exhibited anxiolytic-like effect in the elevated plus-maze test, unaccompanied at anxiolytic doses by the sedative, cognitive impairing, myorelaxant, motor incoordination and anticonvulsant effects commonly associated with classical BZs when tested in the hole-board, step-through passive avoidance, horizontal wire, rotarod, and pentylenetetrazol (PTZ)-induced seizure tests, respectively. The findings therefore identified 6HF as a promising drug candidate for the treatment of anxiety-like disorders.