This study aimed to assess the effects of the antidepressant drug imipramine (IMI) on the neuronal M-type K+ current (IK(M)). We show that IMI reversibly reduces IK(M) with an IC50 of 7 microM. The V0.5 and slope factor of the steady state activation curve remained unchanged after IMI, indicating a mode of action that is voltage insensitive for blocking the M-channel. Patch pipette application of IMI elicits same inhibitory response suggesting a binding site on the M-channel accessible from both sides of the cell membrane. Accordingly, the inhibitory effect of IMI is larger by rising external pH near to the pKa of the drug. Therefore, we propose that a neutral form of IMI binds more efficiently to M-channels to exert its inhibitory action by a voltage-independent mechanism.