The inwardly rectifying K+ (Kir) channel Kir4.1 is responsible for astroglial K+ buffering. We recently found that tricyclic antidepressants (TCAs) inhibit Kir4.1 channel currents, which suggests that astroglial Kir currents might be involved in the pharmacological action of antidepressants. We therefore further examined the effects of the currently most popular antidepressants, selective serotonin reuptake inhibitors (SSRIs), and other related agents on Kir4.1 channels heterologously expressed in HEK293T cells. The whole-cell patch clamp technique was used. Fluoxetine, the typical SSRI, inhibited Kir4.1 channel currents in a concentration-dependent manner with an IC50 value of 15.2 microM. The inhibitory effect of fluoxetine was reversible and essentially voltage-independent. Fluoxetine had little or no effect upon Kir1.1 (ROMK1) or Kir2.1 (IRK1) channel currents. Other SSRIs, sertraline and fluvoxamine, also inhibited Kir4.1 channel currents whereas the tetracyclic (mianserin) or the 5-HT1A receptor-related (buspirone) antidepressants did not. This study shows that SSRIs such as fluoxetine and sertraline preferentially block astroglial Kir4.1 rather than Kir1.1 or Kir2.1 channels in the brain, which may be implicated in their therapeutic and/or adverse actions.