Glutamate is known to increase neuronal excitability in the subfornical organ, a circumventricular organ devoid of the blood-brain barrier. To understand the synaptic mechanism of neuronal excitation by glutamate in this nucleus, we examined the effects of glutamate on GABAergic spontaneous inhibitory postsynaptic currents recorded from subfornical organ neurons in the rat brain slice. The baseline frequency, amplitude and decay time-constant of such spontaneous synaptic currents were 5.60 Hz, 119 pA and 17.3 ms, respectively. Glutamate (10-1000 microM) selectively inhibited the frequency of spontaneous GABAergic inhibitory postsynaptic currents (half-maximal effective concentration=47 microM) with little effects on their amplitudes and decay time constants. The inhibitory effect of glutamate on the frequency of spontaneous GABAergic postsynaptic currents was not blocked by tetrodotoxin (1 microM), or by the antagonists of ionotropic glutamate receptors. In contrast, such inhibitory effect of glutamate was mimicked by general or group II selective metabotropic glutamate receptor agonists such as DCGIV (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (half-maximal effective concentration=112 nM), but not by the agonists for group I or group III metabotropic glutamate receptors. Under current clamp mode, glutamate reduced the frequencies of spontaneous inhibitory postsynaptic potentials and action potentials in subfornical organ neurons. Our data indicate that glutamate decreases the frequency of spontaneous inhibitory postsynaptic currents by acting on the group II metabotropic glutamate receptors on axonal terminals in the subfornical organ. From these results we suggest that the glutamate-induced modulation of tonic GABAergic inhibitory synaptic activity can influence the excitability of subfornical organ neurons.