Traxoprodil, a selective antagonist of the NR2B subunit of the NMDA receptor, potentiates the antidepressant-like effects of certain antidepressant drugs in the forced swim test in mice

One of the newest substances, whose antidepressant activity was shown is traxoprodil, which is a selective antagonist of the NR2B subunit of the NMDA receptor. The main goal of the present study was to evaluate the effect of traxoprodil on animals’ behavior using the forced swim test (FST), as well as the effect of traxoprodil (10 mg/kg) on the activity of antidepressants, such as imipramine (15 mg/kg), fluoxetine (5 mg/kg), escitalopram (2 mg/kg) and reboxetine (2.5 mg/kg). Serotonergic lesion and experiment using the selective agonists of serotonin receptors 5-HT(1A) and 5-HT(2) was conducted to evaluate the role of the serotonergic system in the antidepressant action of traxoprodil. Brain concentrations of tested agents were determined using HPLC. The results showed that traxoprodil at a dose of 20 and 40 mg/kg exhibited antidepressant activity in the FST and it was not related to changes in animals’ locomotor activity. Co-administration of traxoprodil with imipramine, fluoxetine or escitalopram, each in subtherapeutic doses, significantly affected the animals’ behavior in the FST and, what is important, these changes were not due to the severity of locomotor activity. The observed effect of traxoprodil is only partially associated with serotonergic system and is independent of the effect on the 5-HT(1A) and 5-HT(2) serotonin receptors. The results of an attempt to assess the nature of the interaction between traxoprodil and the tested drugs show that in the case of joint administration of traxoprodil and fluoxetine, imipramine or escitalopram, there were interactions in the pharmacokinetic phase

The NMDA receptor ligands in anti-depressant therapy

Wprowadzenie. Nowy kierunek badań nad zaburzeniami depresyjnymi koncentruje się na hamowaniu aktywności receptora NMDA, co stwarza nowe możliwości leczenia chorób wywołanych nadmierną aktywacją układu glutaminianergicznego. Cel pracy. Celem prezentowanej pracy jest przegląd ligandów (w szczególności antagonistów) receptora NMDA działających na jego ekspresję i funkcje oraz ich wpływ na działanie klasycznych leków przeciwdepresyjnych. Opis stanu wiedzy. Skuteczność obecnie stosowanych metod leczenia zaburzeń depresyjnych jest niezadowalająca i obarczona wieloma skutkami ubocznymi. Niepokojący jest również fakt, iż u wielu pacjentów rozwija się lekooporność. Dlatego też opracowuje się nowsze, skuteczniejsze metody leczenia. Wykazano, że jednym z istotnych mechanizmów działania przeciwdepresyjnego jest blokowanie receptora NMDA. Podsumowanie. Wprowadzenie do lecznictwa antagonistów receptora NMDA stwarza nowe możliwości terapeutyczne zaburzeń depresyjnych, a także wydaje się być interesującą alternatywą w leczeniu depresji lekoopornych.A new direction in research on depressive disorders focuses on reducing the activity of the NMDA receptor, which opens up new possibilities for the treatment of diseases caused by the excessive activity of the glutamatergic system. The aim of this work is the study of ligands (especially antagonists) of the NMDA receptor, which influence its expression and function as well as their impact on the action of classic anti-depressant medications. The effectiveness of currently utilized depressive disorder treatment methods is unsatisfactory and linked to many sideeffects. It is also a worrying fact that many patients develop drug resistance. This is why there is a continued effort for the development of newer, more effective treatment methods. It has been shown that one of the key anti-depressant mechanisms of action is through the blockage of the NMDA receptor. The introduction into the treatment regime of antagonists of the NMDA receptor opens new therapeutic possibilities in the treatment of depressive disorders, as well as being a potential alternative in the treatment of drug resistant forms of the disease

Influence of the selective antagonist of the NR2B subunit of the NMDA receptor, traxoprodil, on the antidepressant-like activity of desipramine, paroxetine, milnacipran, and bupropion in mice

Pre-clinical and clinical studies indicated that a blockade of the NMDA receptor complex creates new opportunities for the treatment of affective disorders, including depression. The aim of the present study was to assess the influence of traxoprodil (10 mg/kg) on the activity of desipramine (10 mg/kg), paroxetine (0.5 mg/kg), milnacipran (1.25 mg/kg), and bupropion (10 mg/kg), each at sub-therapeutic doses. Moreover, brain levels of traxoprodil and tested agents were determined using HPLC. The obtained results were used to ascertain the nature of occurring interaction between traxoprodil and studied antidepressants. The experiment was carried out on naïve adult male Albino Swiss mice. Traxoprodil and other tested drugs were administered intraperitoneally. The influence of traxoprodil on the activity of selected antidepressants was evaluated in forced swim test (FST). Locomotor activity was estimated to exclude false positive/negative data. To assess the influence of traxoprodil on the concentration of used antidepressants, their levels were determined in murine brains using HPLC. Results indicated that traxoprodil potentiated activity of all antidepressants examined in FST and the observed effects were not due to the increase in locomotor activity. Only in the case of co-administration of traxoprodil and bupropion, increased bupropion concentrations in brain tissue were observed. All tested agents increased the traxoprodil levels in the brain. Administration of a sub-active dose of traxoprodil with antidepressants from different chemical groups, which act via enhancing monoaminergic transduction, caused the antidepressant-like effect in FST in mice. The interactions of traxoprodil with desipramine, paroxetine, milnacipran, and bupropion occur, at least partially, in the pharmacokinetic phase