ICV injections of streptozotocin (STREP) lower the glucose utilization of the brain and affect the cholinergic system. The present study was designed to evaluate whether STREP-treated rats have an impaired spatial discrimination performance in the Morris spatial navigation task. Performance in this task is sensitive to treatment with cholinergic antagonists. In contrast to young rats, middle-aged STREP-treated rats tended to have an impaired spatial discrimination performance in the Morris task at the end of training. In middle-aged STREP-treated rats, but not in control rats, spatial discrimination performance was associated with hippocampal choline acetyltransferase (ChAT) activity. The correlation between spatial discrimination performance in the Morris task and the decrease in hippocampal ChAT activity resembles the relation between cognitive and biochemical changes observed in Alzheimer's disease. Our findings suggest that STREP treatment of middle-aged rats may provide a relevant model for dementia.