Fluoxetine, widely used for the treatment of depression, is known to be a selective serotonin reuptake inhibitor (SSRI), however, there are also reports that fluoxetine has direct effects on several receptors. Employing whole-cell patch clamp techniques in rat brain slice, we studied the effects of fluoxetine on corticostriatal synaptic transmission by measuring the change in spontaneous excitatory postsynaptic currents (sEPSC). Acute treatment of rat brain slice with fluoxetine (10μM) significantly decreased the amplitude of sEPSC (84.1⁑3.3%, n=7), but did not alter its frequency (99.1⁑4.7%, n=7). Serotonin (10μM) also significantly decreased the amplitude (81.2⁑3.9%, n=4) of sEPSC, but did not affect its frequency (105.8⁑8.0, n=4). The effect of fluoxetine was found to have the same trend as that of serotonin. We also found that the inhibitory effect of fluoxetine on sEPSC amplitude (93.0⁑1.9%, n=8) was significantly blocked, but not serotonin (84.3⁑1.6%, n=4), when the brain slice was incubated with p-chloroamphetamine (10μM), which depletes serotonin from the axon terminals and blocks its reuptake. These results suggest that fluoxetine inhibits corticostriatal synaptic transmission through postsynaptic, and that these effects are exerted through both serotonin dependent and independent mechanism.