Pharmacological evidence for the involvement of the opioid system in the antidepressant-like effect of adenosine in the mouse forced swimming test

This study investigated the involvement of the opioid system in the antidepressant-like effect of adenosine in the forced swimming test. The effect of adenosine (10 mg/kg, i.p.) was prevented by the pretreatment of mice with naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist), naltrindole (3 mg/kg, i.p., a selective δ-opioid receptor antagonist), clocinnamox (1 mg/kg, i.p., an irreversible μ-opioid receptor antagonist), and 2-(3,4-dichlorophenyl)-Nmethyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide (DIPPA; 1 mg/kg, i.p., a selective κ-opioid receptor antagonist), but not with naloxone methiodide (1 mg/kg, s.c., a nonselective opioid receptor antagonist that does not cross the blood–brain barrier). Naloxone also prevented the anti-immobility effect of cyclohexyladenosine (CHA, 0.1 mg/kg, i.p., a selective adenosine A1 receptor agonist) and N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine (DPMA, 1 mg/kg, i.p., a selective adenosine A2A receptor agonist). The administration of DIPPA (0.1 mg/kg, i.p.) or morphine (1 mg/kg, s.c., a nonselective opioid receptor agonist), but not naltrindole (0.3 mg/kg, i.p.) and clocinnamox (0.1 mg/kg, i.p.) potentiated the effect of a subeffective dose of adenosine (1 mg/kg, i.p.) in the forced swimming test, without affecting the locomotor activity. No additive effect in the immobility time was observed when mice were treated with morphine (5 mg/kg, s.c.) plus adenosine (10 mg/kg, i.p.). These results indicate that the anti-immobility effect of adenosine in the forced swimming test, via adenosine A1 and A2A receptors, is mediated by an interaction with the opioid system, likely dependent on an activation of μ- and δ-opioid receptors and an inhibition of κ-opioid receptors.