Agmatine has been proposed as a novel neurotransmitter and modulator in the central nervous system and is abundantly present in the normal hippocampus. It is mainly synthesized in glial cells, and has been found to antagonize the N-methyl-D-aspartate (NMDA) receptor. Decreased hippocampal volumes and reduced glial cell numbers in brain regions have been reported in major depression. Stress-induced hypercortisolemia, which is NMDA receptor dependent, leading to neurotoxicity and/or apoptosis, is the probable cause of hippocampal volume loss or cell death in depression, based on previous studies. The goal of this project is to examine the neuroprotective properties of agmatine against neurotoxicity induced by excitotoxins or higher concentrations of glucocorticoids, which may also occur in major depression. To address this goal, the neuroprotective effects of agmatine will be measured in 1) cultured hippocampal neurons exposed to glutamate as well as related chemicals, 2) the hippocampus from rats treated with excitotoxins and from a rat model of depression. The concentrations of endogenous agmatine in hippocampi will be correlated with the extent of structural injury to neurons and glial cells in the hippocampal primary culture and in the hippocampus of these treated rats and rat model for depression. This research is designed to elucidate the functional significance of agmatine as a novel neurotransmitter of relevance to chronic depression. Clarification of structural and biochemical changes in the hippocampus of an animal model of depression will add to evidence of hippocampal neuron loss in depression, and hopefully suggest ways to augment agmatine’s neuroprotective effects.