For over a decade intensive research has been dedicated to search for NMDA receptor antagonists as a potential neuroprotective treatment for both acute (e.g., stroke) and chronic neurodegenerative diseases. Although only very few such agents reached late stages of clinical development because of side effects, it was discovered that several compounds currently in clinical use such as memantine, amantadine and others have NMDA blocking properties which likely play a role in their therapeutic efficacy. It is still not clear, however, as to how memantine produces its symptomatological improvement of memory in demented patients. The effects of memantine on in vivo hippocampal glutamate levels has not been examined. The followimg investigation was conducted to determine the effects of chronic memantine treatment on hippocampal Glu and GABA release prior to, during, and after spontaneous alternation test. Also, we have investigated the effects of chronic treatment with memantine on basal and KCl-stimulated release of GLU and GABA in the hippocampus. A total of 18 male Wistar rats (Department of Animal Care, I. Beritashvili Center of Experimental Biomedicine) were used in the present study. All experiments were approved by the Animal Care and Use Committee of the Center and were in accordance with the principles of laboratory animal care. Two groups of rats were treated either with memantine (2,5 mg/kg/day; i.p. Sigma Chemical Co., St. Louis, MO) or with vehicle (saline) for a period of 4 weeks. Memantine-treated rats, relative to saline rats, had a significantly lower level in the number of arms entered during the testing session. However, the groups did not differ in the level of alternation behavior. The results indicate that memantine treatment produced decreased locomotor (exploratory) activity (p<0,05) but did not affect spatial working memory in adult rats assessed in spontaneous alternation task (p>0,05). Glu release during the 10 min samples taken at the time of the behavioral testing of memantine or saline treated animals increased during behavioral testing but were not significantly different (p>0,05) from those seen immediately before and after testing. We found increase in KCl-stimulated glutamate and GABA release in the hippocampus of memantine treated rat compared to the saline treated rat. This difference in KCl response between memantine treated and control rat was statistically significant (p<0,05). Our evaluation of memantine reveals that changes in Gluergic neurotransmission after chronic memantine treatment did not affect working memory in adult rats assessed in spontaneous alternation task.