The antidepressant-like effect of guanosine involves the modulation of adenosine A₁ and A_2A receptors

Guanosine has been considered a promising candidate for antidepressant responses, but if this nucleoside could modulate adenosine A₁ (A₁R) and A_2A (A_2AR) receptors to exert antidepressant-like actions remains to be elucidated. This study investigated the role of A₁R and A_2AR in the antidepressant-like response of guanosine in the mouse tail suspension test and molecular interactions between guanosine and A₁R and A₂AR 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 A₁R and reduced A_2AR 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 A₁R/A_2AR antagonist), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX - 2 mg/kg, i.p., a selective adenosine A₁R 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_2AR antagonist). However, the antidepressant-like response of guanosine was completely abolished by adenosine (0.5 mg/kg, i.p., a non-selective adenosine A₁R/A_2AR agonist), N-6-cyclohexyladenosine (CHA - 0.05 mg/kg, i.p., a selective adenosine A₁ 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 A₁R and A_2AR at the adenosine binding site. Overall, this study reinforces the antidepressant-like of guanosine and unveils a previously unexplored modulation of the modulation of A₁R and A_2AR in its antidepressant-like effect.