The antidepressant-like effect of guanosine involves the modulation of adenosine A 1 and A 2A receptors

Guanosine has been considered a promising candidate for antidepressant responses, but if this nucleoside could modulate adenosine A 1 (A 1 R) and A 2A (A 2A R) receptors to exert antidepressant-like actions remains to be elucidated. This study investigated the role of A 1 R and A 2A R in the antidepressant-like response of guanosine in the mouse tail suspension test and molecular interactions between guanosine and A 1 R and A 2 AR by docking analysis. The acute (60 min) administration of guanosine (0.05 mg/kg, p.o.) significantly decreased the immobility time in the tail suspension test, without affecting the locomotor performance in the open-field test, suggesting an antidepressant-like effect. This behavioral response was paralleled with increased A 1 R and reduced A 2A R immunocontent in the hippocampus, but not in the prefrontal cortex, of mice. Guanosine-mediated antidepressant-like effect was not altered by the pretreatment with caffeine (3 mg/kg, i.p., a non-selective adenosine A 1 R/A 2A R antagonist), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX — 2 mg/kg, i.p., a selective adenosine A 1 R antagonist), or 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)-phenol (ZM241385 — 1 mg/kg, i.p., a selective adenosine A 2A R antagonist). However, the antidepressant-like response of guanosine was completely abolished by adenosine (0.5 mg/kg, i.p., a non-selective adenosine A 1 R/A 2A R agonist), N-6-cyclohexyladenosine (CHA — 0.05 mg/kg, i.p., a selective adenosine A 1 receptor agonist), and N-6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)ethyl]adenosine (DPMA — 0.1 mg/kg, i.p., a selective adenosine A 2A receptor agonist). Finally, docking analysis also indicated that guanosine might interact with A 1 R and A 2A R at the adenosine binding site. Overall, this study reinforces the antidepressant-like of guanosine and unveils a previously unexplored modulation of the modulation of A 1 R and A 2A R in its antidepressant-like effect.