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

Abstract

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.

Intrahippocampal injection of a selective blocker of NMDA receptors containing the GluN2B subunit, Ro25‐6981, increases glutamate neurotransmission and induces antidepressant‐like effects

“…This indicates that there could be common mechanisms of action of Ro25-6981 and fluoxetine, independent of adult hippocampal neurogenesis. Other studies assessed in mice the effect of another selective GluN2B subunit antagonist, (1S,2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol; CP-101606 (traxoprodil), at an inactive dose, on the activity of several antidepressant drugs acting through diverse mechanisms, including SRRIs (paroxetine, escitalopram, and fluoxetine) at a subtherapeutic dose [52,53]. The GluN2B subunit antagonist injected intraperitoneally in combination with an antidepressant reduced the immobility duration in the FST, but had no effect alone [52,53].…”

“…Other studies assessed in mice the effect of another selective GluN2B subunit antagonist, (1S,2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol; CP-101606 (traxoprodil), at an inactive dose, on the activity of several antidepressant drugs acting through diverse mechanisms, including SRRIs (paroxetine, escitalopram, and fluoxetine) at a subtherapeutic dose [52,53]. The GluN2B subunit antagonist injected intraperitoneally in combination with an antidepressant reduced the immobility duration in the FST, but had no effect alone [52,53]. These studies confirmed the role of the GluN2B subunit of NMDA receptors in the antidepressant-like effect of SSRIs.…”

Novel Pharmacological Approaches to the Treatment of Depression

“…An NMDAR positive allosteric modulator, AGN-241751, rapidly promoted antidepressant behavior by enhancing GluN2B-NMDA signaling and increasing the concentration of synaptic protein in the medial PFC [155]. Traxoprodil, a GluN2B antagonist, reduced depressive-like behaviors and reinforced the antidepressant effect elicited by conventional MDD treatments such as desipramine, paroxetine, milnacipran, and bupropion [156,157].…”

Traxoprodil Produces Antidepressant-Like Behaviors in Chronic Unpredictable Mild Stress Mice through BDNF/ERK/CREB and AKT/FOXO/Bim Signaling Pathway

“…Traxoprodil is a selective NR2B receptor inhibitor. Administration of a subactive dose of traxoprodil with subactive doses of desipramine, paroxetine, and other traditional antidepressants at subtherapeutic doses led to an antidepressant-like effect in mice [24]. A randomized, placebo-controlled, double-blind study showed that a single dose of traxoprodil significantly improved depressive symptoms and maintained response status for at least 1 week after infusion [25].…”