Agmatine, an endogenous imidazoline receptor ligand modulates ethanol anxiolysis and withdrawal anxiety in rats

Present study investigated the role of agmatine in ethanol-induced anxiolysis and withdrawal anxiety using elevated plus maze (EPM) test in rats. The anxiolytic-like effect of ethanol was potentiated by pretreatment with imidazoline I1/I2 receptor agonist agmatine (10–20 mg/kg, i.p.), imidazoline I1 receptor agonists, moxonidine (0.25 mg/kg, i.p.) and clonidine (0.015 mg/kg, i.p.), imidazoline I2 receptor agonist, 2-BFI (5 mg/kg, i.p.) as well as by the drugs known to increase endogenous agmatine levels in brain viz., l-arginine, an agmatine biosynthetic precursor (100 µg/rat, i.c.v.), ornithine decarboxylase inhibitor, DFMO (125 µg/rat, i.c.v.), diamine oxidase inhibitor, aminoguanidine (65 µg/rat, i.c.v.) and agmatinase inhibitor, arcaine (50 µg/rat, i.c.v.). Conversely, prior administration of I1 receptor antagonist, efaroxan (1 mg/kg, i.p.), I2 receptor antagonist, idazoxan (0.25 mg/kg, i.p.) and arginine decarboxylase inhibitor, d-arginine (100 µg/rat, i.c.v.) blocked the anxiolytic-like effect of ethanol. Moreover, ethanol withdrawal anxiety was markedly attenuated by agmatine (10–20 mg/kg, i.p.), moxonidine (0.25 mg/kg, i.p.), clonidine (0.015 mg/kg, i.p.), 2-BFI (5 mg/kg, i.p.), l-arginine (100 µg/rat, i.c.v.), DFMO (125 µg/rat, i.c.v.), aminoguanidine (65 µg/rat, i.c.v.) and arcaine (50 µg/rat, i.c.v.). The anti-anxiety effect of agmatine in ethanol-withdrawn rats was completely blocked by efaroxan (1 mg/kg, i.p.) and idazoxan (0.25 mg/kg, i.p.). These results suggest that agmatine and imidazoline receptor system may be implicated in ethanol-induced anxiolysis and withdrawal anxiety and strongly support further investigation of agmatine in ethanol dependence mechanism. The data also project agmatine as a potential therapeutic target in overcoming alcohol withdrawal symptoms such as anxiety.