Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and d-cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and d-cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or d-cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and d-cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by d-serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway.

The concomitant administration of certain commonly prescribed antidepressant drugs that affect the serotonergic neurotransmission (i.e., typical tricyclic antidepressants and selective serotonin reuptake inhibitors) with a negative modulator selectively binding to the GluN1/N2B subunits of the NMDA receptor complex (i.e., ifenprodil) may induce a more pronounced antidepressant-like effect than monotherapy. However, these findings still need to be confirmed in further experiments.

The aim of the study was to investigate the modified release of a model substance, of tablets containing different types of Kollidon and particular additives. Additionally, the release kinetics and mechanism of prolonged release of certain tablet preparations were investigated. In this work, tablets containing different types of povidone (Kollidon CL, Kollidon 30, Kollidon SR and other excipients) were prepared by the direct compression technique. The results showed that tablets with fast disintegration and release should contain in their composition, Kollidon CL, lactose and Avicel, however, the use of β-CD instead of lactose or Avicel brings about a slight prolongation in the disintegration time of tablets and the release of an active substance. Furthermore, while other tablet compositions generated within this study must be considered as being prolonged release types, only two of these showed the best fitted mathematical models. The in vitro dissolution data reveal that the dissolution profiles of the two formulations, one containing Kollidon SR with the addition of Kollidon 30, and the second with HPMC K15M, Kollidon 30, Kollidon CL and lactose, best fitted the Higuchi model. Moreover, the release mechanism of these two formulations plotted well into Korsmeyer-Peppas, indicating a coupling of drug diffusion in the hydrated matrix, as well as polymer relaxation – the so-called anomalous transport (non-Fickian).

In the present study, we demonstrated that low, ineffective doses of N-methyl-d-aspartic acid (NMDA) receptor antagonists [competitive NMDA antagonist, CGP 37849, at 0.312 mg/kg intraperitoneally (i.p.), antagonist of the glycineB sites, L-701,324, at 2 mg/kg i.p., partial agonist of glycineB sites, d-cycloserine, at 2.5 mg/kg i.p.] administered jointly with an ineffective dose of the benzodiazepine, chlordiazepoxide (CDP, 2.5 mg/kg i.p.), significantly increased the percentage of time spent in the open arms of the elevated plus-maze (index of anxiolytic effect). Furthermore, CDP-induced anxiolytic-like activity (5 mg/kg i.p.) was antagonized by NMDA (75 mg/kg i.p.) and by an agonist of glycineB sites of the NMDA receptor complex, d-serine [100 nmol/mouse intracerebroventricularly (i.c.v.)]. The present study showed a positive interaction between γ-aminobutyric acid (GABA) and glutamate neurotransmission in the anxiolytic-like activity in the elevated plus-maze test in mice and this activity seems to particularly involve the NMDA receptors.

It is known that tianeptine exhibits antidepressant-like activity. Its influence on the glutamatergic system is also known, but the mechanisms involved in this activity remain to be established. The aim of this study was to investigate the involvement of the glutamate pathway in the antidepressant-like action of tianeptine. We investigated the effects of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor ligands on tianeptine-induced activity in the forced swim test (FST) in mice. The antidepressant-like activity of tianeptine (30 m/kg, ip) was significantly antagonized by D-serine (100 nmol/mouse icv) and NBQX (10 mg/kg, ip). Moreover, low, ineffective doses of the glycine/NMDA site antagonist L-701,324 (1 mg/kg, ip) administered together with low, ineffective doses of tianeptine (20 mg/kg, ip) exhibited a significant reduction of immobility time in the FST. These doses of the examined agents, which did have an effect in the FST, did not alter locomotor activity. The present study indicates that the antidepressant-like activity of tianeptine in the FST involves both NMDA and AMPA receptors and suggests that the interaction between serotonergic and glutamatergic transmission may play an important role in the action of tianeptine.