Antidepressant effects of selective adenosine receptor antagonists targeting the A1 and A2A receptors administered jointly with NMDA receptor ligands: behavioral, biochemical and molecular investigations in mice.

BACKGROUND: The objective of the study was to ascertain the antidepressant potential of the co-administration of NMDA receptor ligands and selective adenosine A1 and A2A receptor antagonists. METHODS: The forced swim test (FST) and spontaneous locomotor activity test were carried out in adult male naïve mice. Before the behavioral testing, animals received DPCPX (a selective adenosine A1 receptor antagonist, 1 mg/kg) or istradefylline (a selective adenosine A2A receptor antagonist, 0.5 mg/kg) in combination with L-701,324 (a potent NMDA receptor antagonist, 1 mg/kg), D-cycloserine (a partial agonist at the glycine recognition site of NMDA receptor, 2.5 mg/kg), CGP 37849 (a competitive NMDA receptor antagonist, 0.3 mg/kg) or MK-801 (a non-competitive NMDA receptor antagonist, 0.05 mg/kg). Additionally, serum BDNF level and the mRNA level of the Adora1, Comt, and Slc6a15 genes in the murine prefrontal cortex were determined. RESULTS: The obtained results showed that DPCPX and istradefylline administered jointly with NMDA receptor ligands (except for DPCPX + D-cycloserine combination) produced an antidepressant effect in the FST in mice without enhancement in spontaneous motility of animals. An elevation in BDNF concentration was noted in the D-cycloserine-treated group. Adora1 expression increased with L-701,324, DPCPX + D-cycloserine, and DPCPX + CGP 37849, while D-cycloserine, CGP 37849, and MK-801 led to a decrease. Comt mRNA levels dropped with DPCPX + L-701,324, istradefylline + L-701,324/CGP 37849 but increased with D-cycloserine, MK-801, CGP 37849 and DPCPX + MK-801/ CGP 37849. Slc6a15 levels were reduced by D-cycloserine, DPCPX + L-701,324 but rose with DPCPX + CGP 37849/MK-801 and istradefylline + D-cycloserine/MK-801/CGP 37849. CONCLUSION: Our study suggests that selective antagonists of adenosine receptors may enhance the antidepressant efficacy of NMDA receptor ligands highlighting a potential synergistic interaction between the adenosinergic and glutamatergic systems. Wherein, A2A receptor antagonists are seen as more promising candidates in this context. Given the intricate nature of changes in BDNF levels and the expression of Adora1, Comt, and Slc6a15 seen after drug combinations exerting antidepressant properties, further research and integrative approaches are crucial understand better the mechanisms underlying their antidepressant action.

Effects of Selen on the Antidepressant-like Activity of Agents Affecting the Adenosinergic Neurotransmission.

The main goal of this study was to determine the antidepressant-like potential of the co-administration of sodium selenite (Se) and the selective adenosine A1 and A2A antagonists DPCPX and istradefylline (IST), respectively, in mice despair tests. Biochemical studies were performed to elucidate the action mechanisms of the investigated treatment strategies. The results confirmed that, when administered by itself, Se exerts an antidepressant-like effect in the FST and TST and that this activity is dose-dependent. Further experiments demonstrated that Se (0.25 mg/kg) significantly enhanced the activity of mice in both tests when co-administered with DPCPX (1 mg/kg) and IST (0.5 mg/kg) at doses which would be ineffective if administered individually. Our research revealed that neither DPCPX, IST, nor Se or combinations of the tested substances induced significant changes in the brain-derived neurotrophic factor (BDNF) levels in mice serum vs. the NaCl-treated group. However, we observed a decrease in the mRNA level of antioxidant defense enzymes. Molecular studies also showed changes in the expression of the Slc6a15, Comt, and Adora1 genes, particularly after exposure to the combination of Se and DPCPX, which indicates a beneficial effect and may help to explain the key mechanism of the antidepressant effect. The combination of Se with substances attenuating adenosine neurotransmission may become a new therapeutic strategy for patients with depression.

The Interaction of Selective A1 and A2A Adenosine Receptor Antagonists with Magnesium and Zinc Ions in Mice: Behavioural, Biochemical and Molecular Studies.

The purpose of the study was to investigate whether the co-administration of Mg2+ and Zn2+ with selective A1 and A2A receptor antagonists might be an interesting antidepressant strategy. Forced swim, tail suspension, and spontaneous locomotor motility tests in mice were performed. Further, biochemical and molecular studies were conducted. The obtained results indicate the interaction of DPCPX and istradefylline with Mg2+ and Zn2+ manifested in an antidepressant-like effect. The reduction of the BDNF serum level after co-administration of DPCPX and istradefylline with Mg2+ and Zn2+ was noted. Additionally, Mg2+ or Zn2+, both alone and in combination with DPCPX or istradefylline, causes changes in Adora1 expression, DPCPX or istradefylline co-administered with Zn2+ increases Slc6a15 expression as compared to a single-drug treatment, co-administration of tested agents does not have a more favourable effect on Comt expression. Moreover, the changes obtained in Ogg1, MsrA, Nrf2 expression show that DPCPX-Mg2+, DPCPX-Zn2+, istradefylline-Mg2+ and istradefylline-Zn2+ co-treatment may have greater antioxidant capacity benefits than administration of DPCPX and istradefylline alone. It seems plausible that a combination of selective A1 as well as an A2A receptor antagonist and magnesium or zinc may be a new antidepressant therapeutic strategy.

Agomelatine and tianeptine antidepressant activity in mice behavioral despair tests is enhanced by DMPX, a selective adenosine A2A receptor antagonist, but not DPCPX, a selective adenosine A1 receptor antagonist.

BACKGROUND: Adenosine, an endogenous nucleoside, modulates the release of monoamines, e.g., noradrenaline, serotonin, and dopamine in the brain. Both nonselective and selective stimulation of adenosine receptors produce symptoms of depression in some animal models. Therefore, the main objective of our study was to assess the influence of a selective adenosine A1 receptor antagonist (DPCPX) and a selective adenosine A2A receptor antagonist (DMPX) on the activity of agomelatine and tianeptine. METHODS: The forced swim test (FST) and tail suspension test (TST) were performed to assess the effects of DPCPX and DMPX on the antidepressant-like activity of agomelatine and tianeptine. Drug serum and brain levels were analyzed using HPLC. RESULTS: Co-administration of agomelatine (20 mg/kg) or tianeptine (15 mg/kg) with DMPX (3 mg/kg), but not with DPCPX (1 mg/kg), significantly reduced the immobility time both in the FST and TST in mice. These effects were not associated with an enhancement in animals' spontaneous locomotor activity. The observed changes in the mouse behavior after concomitant injection of DMPX and the tested antidepressant agents were associated with elevated brain concentration of agomelatine and tianeptine. CONCLUSION: Our study shows a synergistic action of the selective A2A receptor antagonist and the studied antidepressant drugs, and a lack of such interaction in the case of the selective A1 receptor antagonist. The interaction between DMPX and agomelatine/tianeptine at least partly occurs in the pharmacokinetic phase. A combination of a selective A2A receptor antagonist and an antidepressant may be a new strategy for treating depression.

Antidepressant-Like Activity of Typical Antidepressant Drugs in the Forced Swim Test and Tail Suspension Test in Mice Is Augmented by DMPX, an Adenosine A2A Receptor Antagonist.

Unsatisfactory therapeutic effects of currently used antidepressants force to search for new pharmacological treatment strategies. Recent research points to the relationship between depressive disorders and the adenosinergic system. Therefore, the main goal of our studies was to evaluate the effects of DMPX (3 mg/kg, i.p.), which possesses selectivity for adenosine A2A receptors versus A1 receptors, on the activity of imipramine (15 mg/kg, i.p.), escitalopram (2.5 mg/kg, i.p.), and reboxetine (2 mg/kg, i.p.) given in subtherapeutic doses. The studies carried out using the forced swim and tail suspension tests in mice showed that DMPX at a dose of 6 and 12 mg/kg exerts antidepressant-like effect and does not affect the locomotor activity. Co-administration of DMPX at a dose of 3 mg/kg with the studied antidepressant drugs caused the reduction of immobility time in both behavioral tests. The observed effect was not associated with an increase in the locomotor activity. To evaluate whether the observed effects were due to a pharmacokinetic/pharmacodynamic interaction, the levels of the antidepressants in blood and brain were measured using high-performance liquid chromatography. It can be assumed that the interaction between DMPX and imipramine was exclusively pharmacodynamic in nature, whereas an increased antidepressant activity of escitalopram and reboxetine was at least partly related to its pharmacokinetic interaction with DMPX.

DPCPX, a selective adenosine A1 receptor antagonist, enhances the antidepressant-like effects of imipramine, escitalopram, and reboxetine in mice behavioral tests.

The main goal of the present study was to evaluate the influence of the adenosine A1 receptor (A1R) antagonist - DPCPX - on depressive-like behavior in mice, as well as the effect of DPCPX on the activity of imipramine, escitalopram, and reboxetine, each at non-effective doses. The influence of DPCPX on behavior and its influence on the activity of selected antidepressants was evaluated in the forced swim test (FST) and the tail suspension test (TST) in mice. Locomotor activity was measured to verify and exclude false-positive data obtained in the FST and TST. Moreover, serum and brain concentrations of tested antidepressants were determined using HPLC. DPCPX, at doses of 2 and 4 mg/kg, exhibited antidepressant activity in the FST and TST, which was not related to changes in the spontaneous locomotor activity. Co-administration of DPCPX with imipramine, escitalopram, or reboxetine, each at non-active doses, significantly reduced the immobilization period in the FST and TST in mice, which was not due to the increase in locomotor activity. Both antagonists of 5-HT receptors (WAY 100635 and ritanserin) completely antagonized the effect elicited by DPCPX in the behavioral tests. Results of assessment of the nature of the interaction between DPCPX and test drugs show that in the case of DPCPX and imipramine or reboxetine, there were pharmacodynamic interactions, whereas the DPCPX-escitalopram interaction is at least partially pharmacokinetic in nature. Presented outcomes indicate that an inhibition of A1Rs and an increase of monoaminergic transduction in the CNS may offer a novel strategy for the development of antidepressant drugs.

The influence of selective A1 and A2A receptor antagonists on the antidepressant-like activity of moclobemide, venlafaxine and bupropion in mice.

OBJECTIVE: The main goal of our study was to investigate whether a selective antagonism of the adenosine A1 or A2A receptors is able to enhance the antidepressant activity of commonly prescribed drugs. MATERIALS AND METHODS: All experiments were carried out on male Albino Swiss mice. The forced swim test and the tail suspension test were used to evaluate the antidepressant-like potential. Drug concentrations in animals' serum and brains were measured by high-performance liquid chromatography. KEY FINDINGS: The antidepressant potential of moclobemide (1.5 mg/kg), venlafaxine (1 mg/kg) and bupropion (10 mg/kg) was enhanced by a co-administration with 3,7-dimethyl-1-propargylxanthine (DMPX; an antagonist of adenosine A2A receptors; 3 mg/kg) or 8-cyclopentyl-1,3-dipropylxanthine (an antagonist of adenosine A1 receptors; 1 mg/kg). However, significant interactions between the tested substances were detected only in the experiments with DMPX. The nature of the observed interplays is rather pharmacodynamic than pharmacokinetic, because neither serum nor brain concentrations of the used drugs were significantly increased. CONCLUSIONS: Blockage of the adenosine receptors (particularly the A2A subtypes) could be considered in future as a novel, promising part of the combined antidepressant therapy. However, further studies on this subject are needed.

Caffeine augments the antidepressant-like activity of mianserin and agomelatine in forced swim and tail suspension tests in mice.

BACKGROUND: The main goal of this research was an evaluation of the influence of caffeine on the activity of mianserin and agomelatine. METHODS: The mouse forced swim test and tail suspension test were used to determine the influence of caffeine on the activity of the tested drugs. Drug concentrations in serum and brains were estimated by HPLC. RESULTS: Caffeine increases the anti-immobility action of mianserin and agomelatine. The observed effects were not associated with changes in the level of drugs in serum or brains. CONCLUSION: The synergistic effect of caffeine and the tested drugs may be associated with their summative actions on monoaminergic neurotransmission. Caffeine-mianserin and caffeine-agomelatine interactions might have been of pharmacodynamic origin.