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Depression is one of the most common psychiatric disorders which is a leading cause of total disability and economic burden. Although there are medications that alleviate depressive symptoms, they have serious limitations. Therefore better understanding of the neurobiology of the disease is required. Agmatine (l-amino-4-guanidinobutane) is an endogenous amine synthesized from the decarboxylation of arginine. Agmatine has been quantified in nearly all of the organs of the rat including brain and plasma. Agmatine exerts a wide range of biological activities on several organ systems, including the central nervous system, where it has been proposed to act as a neurotransmitter. Agmatine interacts with the imidazoline receptors, alpha-2-adrenoceptors, nicotinic cholinergic receptors, and serotonergic 5-HT3 receptors. It selectively modulates the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors in rat hippocampal neurons via an interaction between the guanidino group of agmatine and the NMDA channel pore and is an endogenous inhibitor of all isoforms of nitric oxide synthase. Agmatine is released from neurons and has neuroprotective properties. The present study was designed to evaluate the effect of agmatine in a chronic unpredictable mild stress (CUMS)-induced depression model. Animals were allocated to the following study groups: animals not exposed to CUMS (Control group, n=12), animals exposed to CUMS for 5 weeks (CUMS group, n=12), and animals exposed to CUMS and treated with agmatine (CUMS+Agmatine group, n=12). The control and CUMS groups were injected with saline and the CUMS+Agmatine group was injected with agmatine 40 mg/kg, i.p. daily throughout the experiment. CUMS was applied as previously described with a minor modification. Brieşy, the CUMS and CUMS+Agmatine groups were subjected to different types of stressors: restraint for 4 h, cage tilting for 24 h, wet bedding for 24 h, swimming in 40C cold water for 5 min, swimming in 45 C hot water for 5 min, pairing with another stressed animal for 48 h, level shaking for 10 min, nip tail for 1 min, and inversion of the light/dark cycle for 24 h. These nine stressors were randomly applied for 5 weeks, during which each stressor was applied for 4-5 times. The rats received one of these stressors per day and the same stressor was not applied continuously for 2 days so that animals could not predict the occurence of stimulation. The control group not receiving stress treatment had free access to food and water but all groups were food and water deprived 24 h before the sucrose consumption test only. After 5 weeks, the sucrose consumption, sucrose preference and forced swimming tests were performed. The results of this study showed that agmatine administration during CUMS suppressed CUMS-induced depression-like behavioral changes, including a reduction in sucrose preference, body weight, locomotor activity, and a decrease in immobility time in the forced swimming test. Our findings suggest that agmatine may have a protective effect either by inhibiting oxidative damage and/or by modulating neuronal activity in CUMS. Based on these findings, agmatine, as an endogenous molecule, has a promising effect and further studies are required to understand the underlying mechanism.