The aim of the study was to investigate the participation of ionotropic glutamatergic receptors in the mechanism of action of antidepressant drugs. Imipramine, fluoxetine, milnacipran, escitalopram and reboxetine were choosen to the experiments. The forced swim test (Porsolt test) was performed on mice to investigate the antidepressant activity of compounds. The dose response effect was demonstrated. The antidepressants were administered togerher with the ligands of ionotropic glutamatergic receptors: N-methyl-d-aspartic acid and CGP3748 (NMDA agonist and antagonist) and CX614 and NBQX (positive allosteric modulator and antagonist of AMPA). Moreover, the locomotor activity of animals was also examined. Further examination was carried out on rats. The animals were administered with imipramine, fluoxetine, escitalopram and milnacipran for 14 days. The objective of the study was to determine the influence of the chronic administration of antidepressants on the level of GluN2A, GluN2B (NMDA receptor) and GluA1 (AMPA receptor) subunits in the cerebral cortex. The investigation was performed using western blotting method.The results show that the NMDA receptor antagonist – CGP37849 – increase the antidepressant-like activity of tested drugs with the exception of fluoxetine. The NMDA receptor agonist inhibits the activity of escitalopram and milnacipran in Porsolt test. The imipramine and reboxetine activity was increased by the ampakine CX614. The AMPA receptor antagonist did not influence the antidepressant action of any of the examined drugs in the forced swim test. The chronic administration of the drugs did not change the level of the investigated subunits.The data obtained in the present study allowed to know the mechanisms of action of antidepressant drugs better and provide further evidence for the involvement of glutamatergic system in their action. The importance is synergistic activity of CGP37849 with antidepressants of both noradrenergic and serotonergic profile. Supplementation with NMDA receptor antagonists of antidepressant therapy would enhance its efficacy, and what is particularly important in the treatment resistant depression.