Inhibitory influence of agmatine in ethanol withdrawal-induced depression in rats: Behavioral and neurochemical evidence.

Although ethanol withdrawal depression is one of the prominent reasons for ethanol consumption reinstatement and ethanol dependence, its neurochemical basis is not clearly understood. The present study investigated the role of the agmatinergic system in ethanol withdrawal-induced depression using the forced swim test (FST) in rats. Chronic exposure of animals to ethanol for 21 days and its abrupt withdrawal produced depression-like behavior, as evidenced by increased immobility time in the FST, compared to the pair-fed control animals. The ethanol withdrawal-induced depression was significantly attenuated by agmatine (20-40 μg/rat, i.c.v. [intracerebroventricularly]), moxonidine (50 μg/rat, i.c.v.), 2-BFI (20 μg/rat, i.c.v.), L-arginine (80 μg/rat, i.c.v.), amino-guanidine (25 μg/rat, i.c.v.), and arcaine (50 μg/rat, i.c.v.) by their once-daily administration during the withdrawal phase (Days 21, 22, and 23). The antidepressant effect of agmatine in ethanol-withdrawn rats was potentiated by the imidazoline receptor I1 agonist moxonidine (25 μg/rat, i.c.v.) and the imidazoline receptor I2 agonist, 2-BFI (10 μg/rat, i.c.v.) at their sub-effective doses. On the other hand, it was completely blocked by the imidazoline receptor I1 antagonist, efaroxan (10 μg/rat, i.c.v.) and the imidazoline receptor I2 antagonist, idazoxan (4 μg/rat, i.c.v.). In addition, agmatine levels were significantly reduced in brain samples of ethanol-withdrawn rats as compared to the pair-fed control animals. In conclusion, the present study suggests the importance of the endogenous agmatinergic system and the imidazoline receptors system in ethanol withdrawal-induced depression. The data project agmatine as a potential therapeutic target for the alcohol withdrawal-induced depression.