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.
Subject(s)
Antidepressive Agents/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Piperidines/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Analysis of Variance , Animals , Antidepressive Agents/pharmacokinetics , Brain/drug effects , Brain/metabolism , Bupropion/pharmacokinetics , Bupropion/pharmacology , Chromatography, High Pressure Liquid , Cyclopropanes/pharmacokinetics , Cyclopropanes/pharmacology , Depressive Disorder/drug therapy , Depressive Disorder/metabolism , Desipramine/pharmacokinetics , Desipramine/pharmacology , Disease Models, Animal , Drug Interactions , Excitatory Amino Acid Antagonists/pharmacokinetics , Injections, Intraperitoneal , Male , Mice , Milnacipran , Motor Activity/drug effects , Paroxetine/pharmacokinetics , Paroxetine/pharmacology , Piperidines/pharmacokineticsABSTRACT
BACKGROUND: The main objective of our study was to evaluate the influence of traxoprodil on the activity of the atypical antidepressant drugs (agomelatine, mianserin, tianeptine). METHODS: The forced swim test (FST) in mice was used to determine the antidepressant-like activity of the tested agents. Drugs levels in brain tissue were assessed by a high performance liquid chromatography method. RESULTS: Concurrent intraperitoneal administration of per se ineffective doses of traxoprodil (10mg/kg) and agomelatine (20mg/kg) shortened the immobility time of animals in the FST. The observed effect was associated with elevated brain levels of traxoprodil. Similar interaction was not detected for traxoprodil and mianserin (10mg/kg) or tianeptine (15mg/kg). CONCLUSION: Traxoprodil-agomelatine interaction is pharmacokinetic in nature. A combination of these agents has a potential to become an interesting strategy in the treatment of depression.
Subject(s)
Acetamides/pharmacology , Antidepressive Agents/pharmacology , Depression/drug therapy , Depressive Disorder/drug therapy , Mianserin/pharmacology , Piperidines/pharmacology , Thiazepines/pharmacology , Animals , Brain/drug effects , Drug Synergism , Male , Mice , Motor Activity/drug effects , Swimming/physiologyABSTRACT
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-HT1A and 5-HT2 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-HT1A and 5-HT2 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.
