Antidepressant-like action of agmatine in the acute and sub-acute mouse models of depression: a receptor mechanism study

Previous studies have shown that agmatine, a potential neuromodulator or co-transmitter, exhibited antidepressant-like action in animal models, yet its mechanism, especially the receptor mechanism, remains unclear. In the present study, using efaroxan, a preferential antagonist of I₁ imidazoline receptor (I₁R) and yohimbine, an antagonist of α₂ adrenergic receptor (α₂AR), we investigated the roles of I₁R and α₂AR in agmatine’s antidepressant-like effect in acute and sub-acute depression models in mice. We found that in the tail-suspension test (TST) and the forced swimming test (FST), acute administration of agmatine (20 and 40 mg/kg, p.o.) significantly shortened the immobility time. Concurrent administration of efaroxan (1 mg/kg, i.p.) completely abolished the antidepressant-like effects of agmatine (40 mg/kg, p.o.) whereas yohimbine (5 mg/kg, i.p.) failed to exert similar effects, suggesting that the acute antidepressant-like effects of agmatine was mainly mediated by I₁R but not α₂AR. Additionally, in the learned helplessness (LH) test, repeated administration of agmatine (20 mg/kg, p.o., q.d.) for 5 days significantly decreased the escape latency and the number of escape failure, and these effects were respectively abolished by concurrent administration of efaroxan (0.5 mg/kg,i.p., q.d.) and yohimbine (3 mg/kg, i.p., q.d.) for 5 days, suggesting that the antidepressant-like action of agmatine in the LH test was achieved via the activation of both I₁R and α₂AR. In summary, we found that the antidepressant-like effects of agmatine in the TST and the FST were mediated by activating I₁R and in the sub-acute LH test were mediated by activating both I₁R and α₂AR.