Short communication Involvement of NMDA and AMPA receptors in the antidepressant-like activity of antidepressant drugs in the forced swim test Ma³gorzata Wolak 1 , Agata Siwek 1 , Bernadeta Szewczyk 4 , Ewa Poleszak 5 , Andrzej Pilc 2,4 , Piotr Popik 2 , Gabriel Nowak 1,4 Correspondence: Abstract: Background: The involvement of glutamate system (particularly the NMDA and AMPA receptors) in the mechanism of antidepres- sant activity was demonstrated in preclinical and clinical studies. Methods: In the present study, we investigate the effect of NMDA and AMPA receptors’ ligands (agonists and antagonists) on antidepressant-like activity of escitalopram, milnacipran, imipramine and reboxetine in the forced swim test in mice. Results: Antidepressant activity (reduction in immobility time) of escitalopram and milnacipran but not of imipramine and reboxet- ine was antagonized by N-methyl-D-aspartate acid. CGP37849 (antagonist of the NMDA receptor) enhanced the antidepressant ac- tivity of all examined antidepressants. On the other hand, CX614 (a potentiator/positive allosteric modulator of the AMPA receptor) enhanced the antidepressant activity of imipramine and reboxetine but not of escitalopram and milnacipran in this test. NBQX (the AMPA receptor antagonist) did not influence the antidepressant activity of all tested agents. Conclusions: The data indicate the complex interactions following the activation or blockade of the NMDA and AMPA receptors with antidepressant drugs. The general phenomenon is the enhancing effect of the NMDA receptor antagonism on the antidepressant activ- ity. Moreover, is can be concluded that the activity of antidepressants with a serotonergic mechanism of action can be inhibited by NMDA activation , while antidepressants with a noradrenergic mechanism of action are dependent on AMPA receptor transmission. Key words: antidepressants, NMDA, AMPA, ligands, forced swim test, mice Introduction Several lines of evidence suggest the involvement of ionotropic AMPA and NMDA glutamate receptors in the mechanism of action of antidepressant drugs [13, 18]. This evidence is bidirectional in that both chronic treatment with antidepressants affects the function of glutamate receptors, and antagonists of NMDA recep- tors as well as positive allosteric modulators of AMPA 991