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 A(1) receptor antagonist (DPCPX) and a selective adenosine A(2A) 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 A(2A) receptor antagonist and the studied antidepressant drugs, and a lack of such interaction in the case of the selective A(1) receptor antagonist. The interaction between DMPX and agomelatine/tianeptine at least partly occurs in the pharmacokinetic phase. A combination of a selective A(2A) receptor antagonist and an antidepressant may be a new strategy for treating depression. (C) 2019 Maj Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.