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.
Highlights
One of the new approaches to the treatment of depression is focused on glutamatergic neurotransmission
The main goal of this study was to assess the effect of traxoprodil, at the inactive dose, on the activity of antidepressant drugs acting through diverse mechanisms, i.e., desipramine—the tricyclic antidepressant (TCA), paroxetine—a selective serotonin reuptake inhibitor (SSRI), milnacipran selective serotonin and norepinephrine reuptake inhibitor (SNRI), and bupropion—a norepinephrine–dopamine reuptake inhibitor (NDRI) in forced swim test (FST) in mice
The observed in present study enhancement of milnacipran activity when co-administered with traxoprodil seem to confirm the results presented by Wolak et al (2013) that indicated the strengthening of antidepressant action of milnacipran by concomitant application of CGP 27849 (NMDA receptor antagonist)
Summary
One of the new approaches to the treatment of depression is focused on glutamatergic neurotransmission. Previous preclinical studies indicate that the NMDA receptor ligands (e.g., CGP 37849, CGP 39551, MK-801, kynurenic acid, 7-chlorokynurenic acid, zinc, magnesium) possess antidepressant-like activity in animal tests and models of depression (Eby and Eby 2010; Maj et al 1992a, b; Nowak et al 2003; Poleszak et al.2005, 2011; Szewczyk et al 2009), whereas ketamine and memantine are already used successfully in humans (Berman et al 2000; Keck et al 2009; Zarate et al 2006). Serious side effects such as memory loss, ataxia, and an increase in motor activity related to the application of certain ligands of the NMDA receptor precludes its therapeutic use in humans (Willetts et al 1990). The results of this study have indicated that traxoprodil has a greater therapeutic potential with no adverse effects on the learning and memory (Guscott et al 2003). Literature data have shown promising results that confirm the usefulness of traxoprodil in the treatment of depression, and in one study the rapid improvement of mental health in patients who were previously treated unsuccessfully with paroxetine has been described (Preskorn et al 2008)
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