The antidepressant-like effect of guanosine involves the modulation of adenosine A1 and A2A 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.