Several antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a non-competitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological profile modulate the rat alpha 7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording of the ion current elicited by choline, I-Ch, which activates alpha 7 nAChRs from rat CA1 hippocampal interneurons) and in silico approaches (homology modeling of the rat alpha 7 nAChR, molecular docking, molecular dynamics simulations, and binding free energy calculations). The antidepressants inhibited I-Ch with the order: norfluoxetine similar to mirtazapine similar to imipramine < bupropion similar to fluoxetine similar to venlafaxine similar to escitalopram. The constructed homology model of the rat alpha 7 nAChR resulted in the extracellular vestibule and the channel pore is highly negatively charged, which facilitates the permeation of cations and the entrance of the protonated form of antidepressants. Molecular docking and molecular dynamics simulations were carried out within the ion-channel of the alpha 7 nAChR, revealing that the antidepressants adopt poses along the receptor channel, with slightly different binding-free energy values. Furthermore, the inhibition of I-Ch and free energy values for each antidepressant-receptor complex were highly correlated. Thus, the alpha 7 nAChR is negatively modulated by a variety of antidepressants interacting in the ion-channel.