Quercetin is a substance of low molecular weight found in vascular plants with a wide range of biological activities including antioxidative and anti-inflammatory activities. In the present study, the effects of quercetin on native glycine receptors (GlyRs) in cultured rat hippocampal neurons were investigated using a whole-cell patch-clamp technique. Quercetin reversibly and concentration-dependently depressed glycine-induced current (I(Gly)), with an IC50 of 10.7+/-0.24 microM and a Hill coefficient of 1.08+/-0.12. Quercetin depressed maximum I(Gly) and significantly changed the EC50 for glycine and the Hill coefficient. Kinetic analysis indicated that quercetin accelerated the rates of desensitization. Interestingly, after the end of glycine with quercetin coapplication, a transient rebound occurred. The quercetin effects also displayed voltage-dependence, being greater at positive membrane potentials. These effects suggested that quercetin may act as an open channel blocker. Furthermore, in the sequential application protocol, quercetin inhibited the peak amplitude of I(Gly) to a macroscopic degree while slowing GlyR desensitization. These effects implied that quercetin has a depressant effect independent of GlyR channel's opening, which maybe caused by an allosteric mechanism. Strikingly, quercetin inhibited the amplitude of recombinant-induced current mediated by alpha2-, alpha2beta-, alpha3- and alpha3beta-GlyRs but had no effects on alpha1- and alpha1beta-GlyRs that were expressed in HEK293T cells. We also investigated the effects of quercetin on I(Gly) in spinal neurons during development in vitro. The extent of blockade by quercetin on I(Gly) was slighter in spinal neurons than in hippocampal neurons in a development-dependent manner. Taken together, our results suggest that quercetin has possible effects in information processing within a neuronal network by inhibition of I(Gly) and may be useful as a pharmacological probe for identifying the subunit types of GlyRs.