Dose Of N-methyl-d-aspartate Receptor Antagonist Research Articles

Involvement of NMDA receptors in the antidepressant-like effect of tramadol in the mouse forced swimming test.

Tramadol is an analgesic agent that is mainly used to treat moderate to severe pain. There is evidence that tramadol may have antidepressant property. However, the mechanisms underlying the antidepressant effects of tramadol have not been elucidated yet. Considering that fact that N-methyl-d-aspartate (NMDA) receptor signaling may play an important role in the pathophysiology of depression, the aim of the present study was to investigate the role of NMDA receptor signaling in the possible antidepressant-like effects of tramadol in the mouse forced swimming test (mFST). We found that tramadol exerted antidepressant-like effects at high dose (40mg/kg, intraperitoneally [i.p.]) in the mFST. Co-administration of non-effective doses of NMDA receptor antagonists (ketamine [1mg/kg, i.p.], MK-801 [0.05mg/kg, i.p.], or magnesium sulfate [10mg/kg, i.p.]) with sub-effective dose of tramadol (20mg/kg, i.p.) exerted significant antidepressant-like effects in the mFST. The antidepressant-like effects of tramadol (40mg/kg) was also inhibited by pre-treatment with non-effective dose of the NMDA receptor agonist NMDA (75mg/kg, i.p.). Our data suggest a role for NMDA receptor signaling in the antidepressant-like effects of tramadol in the mFST.

Involvement of N-methyl-d-aspartate receptors in the antidepressant-like effect of 5-hydroxytryptamine 3 antagonists in mouse forced swimming test and tail suspension test

Recent evidence indicates that 5-hydroxytryptamine 3 (5-HT3) antagonists such as ondansetron and tropisetron exert positive behavioral effects in animal models of depression. Due to the ionotropic nature of 5-HT3 and N-methyl-d-aspartate (NMDA) receptors, plus their contribution to the pathophysiology of depression, we investigated the possible role of NMDA receptors in the antidepressant-like effect of 5-HT3 receptor antagonists in male mice. In order to evaluate the animals' behavior in response to different treatments, we performed open-field test (OFT), forced swimming test (FST), and tail-suspension test (TST), which are considered as valid tasks for measuring locomotor activity and depressive-like behaviors in mice. Our data revealed that intraperitoneal (i.p.) administration of tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01, and 0.1μg/kg) significantly decreased the immobility time in FST and TST. Also, co-administration of subeffective doses of tropisetron (1mg/kg, i.p.) or ondansetron (0.001μg/kg, i.p.) with subeffective doses of NMDA receptor antagonists, ketamine (1mg/kg, i.p.), MK-801 (0.05mg/kg, i.p.) and magnesium sulfate (10mg/kg, i.p.) resulted in a reduced immobility time both in FST and TST. The subeffective dose of NMDA (NMDA receptor agonist, 75mg/kg, i.p.) abolished the effects of 5-HT3 antagonists in FST and TST, further supporting the presumed interaction between 5-HT3 and NMDA receptors. These treatments did not affect the locomotor behavior of animals in OFT. Finally, the results of our study suggest that the positive effects of 5-HT3 antagonists on the coping behavior of mice in FST and TST are at least partly mediated through NMDA receptors participation.

Evidence for the involvement of NMDA receptors in the antidepressant-like effect of nicotine in mouse forced swimming and tail suspension tests.

The antidepressant action of acute nicotine administration in clinical and animal studies is well recognized. But the underlying mechanism for this effect has not been carefully discovered. We attempted to evaluate the possible role of N-Methyl-D-aspartate (NMDA) receptors in the antidepressant-like effect of nicotine. After the assessment of locomotor activity in the open-field test, forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant-like effect of nicotine in mice. We performed intraperitoneal administration of nicotine at different doses and periods before the tests. To assess the possible involvement of NMDA receptors, non-effective doses of NMDA antagonists and an NMDA agonist were obtained and were administered simultaneously with the non-effective and effective doses of nicotine, respectively. Nicotine (0.2mg/kg, 30min before FST/TST) significantly reduced the immobility time of mice similar to fluoxetine (20mg/kg). Nicotine did not affect the locomotor behavior of mice in open-field test. Co-administration of non-effective doses of NMDA receptor antagonists, ketamine (1 or 0.3mg/kg), MK-801 (0.05 or 0.005mg/kg), and magnesium sulfate (10 or 5mg/kg) with nicotine (0.1 or 0.03mg/kg) had remarkable synergistic antidepressant effect in both FST and TST. Also, non-effective NMDA (75 or 30mg/kg) reversed the anti-immobility effect of nicotine (0.2mg/kg) on mouse FST and TST. Our study has for the first time confirmed that the antidepressant-like effect of nicotine on mice is NMDA-mediated, and nicotine presumably exerts this effect by antagonizing the glutamatergic NMDA receptors.

Lowered brain stimulation reward thresholds in rats treated with a combination of caffeine and N-methyl-D-aspartate but not alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate or metabotropic glutamate receptor-5 receptor antagonists

Previous studies suggested that adenosine A1 and A2A receptor agonists counteract behavioral effects of N-methyl-D-aspartate (NMDA) receptor antagonists while adenosine receptor antagonists may produce opposite effects enhancing the actions of NMDA receptor antagonists. To further evaluate the effects of combined administration of adenosine receptor antagonist caffeine and various NMDA and non-NMDA glutamate receptor antagonists on brain stimulation reward (discrete-trial threshold current intensity titration procedure), rats with electrodes implanted into the ventral tegmental area were tested after pretreatment with NMDA receptor channel blocker MK-801 (0.01-0.3 mg/kg), competitive antagonist D-CPPene (0.3-5.6 mg/kg), glycine site antagonist L-701,324 (1.25-5 mg/kg), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist GYKI-53655 (1-10 mg/kg), metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP (1-10 mg/kg) alone and in combination with caffeine (1-30 mg/kg). MK-801 (0.056 and 0.1 mg/kg) was the only tested glutamate antagonist that lowered self-stimulation thresholds, while D-CPPene (5.6 mg/kg) and MPEP (5.6 and 10 mg/kg) had the opposite effects. Threshold-increasing effects of D-CPPene, but not of MPEP, however, were associated with marked impairment of operant performance, reflected by longer latencies to respond and higher rates of responding during the inter-trial intervals. Operant performance was also disrupted by the highest dose of MK-801 (0.3 mg/kg). For subsequent experiments, caffeine (1-30 mg/kg) was combined with the highest doses of NMDA receptor antagonists that did not lower the brain stimulation reward thresholds and did not impair operant performance. Caffeine had no appreciable effects on self-stimulation behavior when given alone. A low dose of caffeine (3 mg/kg) significantly lowered self-stimulation thresholds only when given together with MK-801 (0.03 mg/kg) or D-CPPene (3 mg/kg). Combined with the same antagonist drugs, higher doses of caffeine (10 and 30 mg/kg) facilitated time-out responding. These results indicate that, within a limited dose range, caffeine in combination with an NMDA receptor channel blocker and a competitive antagonist significantly lowers brain stimulation reward thresholds in rats.

Suppression of NMDA receptor function using antisense DNA block ocular dominance plasticity while preserving visual responses.

Pioneering work has shown that pharmacological blockade of the N-methyl-D-aspartate (NMDA) receptor channel reduces ocular dominance plasticity. However, the results also show that doses of NMDA receptor antagonists that have an effect on ocular dominance plasticity profoundly reduce sensory responses and disrupt stimulus selectivity of cortical cells. It is, therefore, not possible to determine whether effects of NMDA receptor blockade on visual plasticity result from a specific role of NMDA receptors or from the reduction in sensory response. We have used an alternate approach to examine this question. We performed knockdown experiments using antisense oligodeoxynucleotides (ODNs) complementary to mRNA coding the NR1 subunit of the NMDA receptor. After 5 days of antisense, but not sense, ODN treatment NMDA receptor-mediated synaptic transmission was reduced markedly relative to the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor response, as indicated by whole cell patch-clamp recordings in the cortical slice preparation. This suppression of NMDA receptor-mediated currents was due to a selective reduction in the NR1 protein near the injection site relative to the untreated hemisphere in the same animal, as indicated by immunocytochemistry and Western blotting. In contrast, AMPA receptors were not affected by the antisense ODN treatment indicating specificity of effects. Another major effect of this treatment was to decrease ocular dominance plasticity. Ferrets that were monocularly deprived 1 wk during the antisense ODN treatment had ocular dominance histograms similar to those found in untreated, nondeprived animals. In contrast, ferrets treated with sense ODN and monocularly deprived had ocular dominance histograms resembling those of untreated, monocularly deprived animals. The effects on ocular dominance plasticity did not result from a disruption of sensory responses because maximum responses as well as orientation and direction selectivity of cortical cells were not affected by the treatment. In conclusion, the present results show that antisense techniques can accomplish more selective manipulations of cortical function than is possible with traditional pharmacological agents. Use of this approach also provides unambiguous evidence for a specific role of NMDA receptors in visual plasticity.

Low doses of NMDA receptor antagonists synergistically increase the anticonvulsant effect of the AMPA receptor antagonist NBQX in the kindling model of epilepsy.

Excitatory amino acid transmitters are involved in the initiation of seizures and their propagation. Most attention has been directed to synapses using N-methyl-D-aspartate (NMDA) receptors, although more recent evidence indicates potential roles for the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors as well. In the present experiments in amygdala-kindled rats, i.e. a model of partial epilepsy, competitive and uncompetitive NMDA antagonists exerted only weak anticonvulsant effects, whereas the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX) potently increased focal seizure threshold and inhibited seizure spread from the focus. These effects of NBQX were dramatically increased by pretreatment with low doses of NMDA antagonists, whereas adverse effects of NBQX were not potentiated. These data suggest that both non-NMDA and NMDA receptors are critically involved in the kindled state, and that combinations of AMPA and NMDA receptor antagonists provide a new strategy for treatment of epileptic seizures.