Extensive evidence suggests that glucose has both positive and negative effects on memory and these effects likely involve an influence on the brain. For instance, direct infusions of glucose into the septum (MS) or hippocampus can enhance or impair memory. The present set of experiments attempted to determine the different conditions that dissociate the memory-enhancing and -impairing effects of glucose in rats. Specifically, these experiments examined the effects of glucose in spontaneous alternation, a measure of spatial working memory and shock avoidance, an index of emontional long-term memory. The results showed that the memory-impairing effects of MS infusions of glucose are not concentration-dependent. These data also indicated that the memory-impairing effects of MS glucose elevations are specific to gamma-aminobutyric acid GABA receptor activation but do not depend on increases in MS GABA synthesis or release. Importantly, we showed that the memory-impairing interaction between MS glucose and GABA agonists does not generalize to the hippocampus, suggesting the memory-modulating effects of glucose are brain region-dependent. We showed further that these brain region-dependent effects of glucose are not due to difference in basal extracellular glucose levels. Moreover, these findings showed that the memory-enhancing effects of hippocampus glucose override the memory-impairing interaction between MS glucose and GABA. These findings are important because they are the first to show that the memory-modulating effects of glucose are both neurotransmitter- and brain region-dependent. Furthermore, these findings provide preliminary evidence suggesting that the memory-impairing effects of MS glucose may involve compromised hippocampal function. These data also suggest the memory-impairing effects of MS co-infusions of glucose with GABA agonists likely involve an influence on the GABAergic SH projection. Finally, these findings demonstrate the mnemonic and neurochemical consequences of glucose in the MS and hippocampus, two brain regions affected by normal aging, Alzheimer’s disease, and diabetes.