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The antidepressant-like activity of creatine in the tail suspension test (TST) was demonstrated previously by our group. In this study we investigated the involvement of the noradrenergic system in the antidepressant-like effect of creatine in the mouse TST. In the first set of experiments, creatine administered by i.c.v. route (1μg/site) decreased the immobility time in the TST, suggesting the central effect of this compound. The anti-immobility effect of peripheral administration of creatine (1mg/kg, p.o.) was prevented by the pretreatment of mice with α-methyl-p-tyrosine (100mg/kg, i.p., inhibitor of tyrosine hydroxylase), prazosin (1mg/kg, i.p., α₁-adrenoceptor antagonist), but not by yohimbine (1mg/kg, i.p., α₂-adrenoceptor antagonist). Creatine (0.01mg/kg, subeffective dose) in combination with subeffective doses of amitriptyline (1mg/kg, p.o., tricyclic antidepressant), imipramine (0.1mg/kg, p.o., tricyclic antidepressant …