Using in vivo microdialysis, we measured hippocampal extracellular glucose concentrations in rats while they performed spontaneous alternation tests of spatial working memory in one of two mazes. Extracellular glucose levels in the hippocampus decreased by 32% below baseline during the test period on the more complex maze, but by a maximum of 11% on the less complex maze. Comparable decreases were not observed in samples taken from rats tested on the more complex maze but with probes located near but outside of the hippocampus. Systemic glucose fully blocked any decrease in extracellular glucose and enhanced alternation on the more complex maze. These findings suggest that cognitive activity can deplete extracellular glucose in the hippocampus and that exogenous glucose administration reverses the depletion while enhancing task performance.T raditional models of the distribution of glucose through the brain make two key statements: first, that the level of glucose is the same throughout the brain, which is viewed as a single compartment with respect to glucose; and second, that this level is invariant, with transport capacity always exceeding demand (1-3). Such models pose significant problems for interpretation of the large body of data showing that administration of glucose, either peripherally or directly into the brain, produces dosedependent effects on cognition, including enhancement of memory in a range of tasks (4-11). Most potential mechanisms for glucose effects on cognition, such as provision of additional energy, provision of additional substrate for neurotransmitters, and modulation of transmitter release, require that glucose administration lead to increased extracellular glucose availability in the brain. Moreover, because neuronal enzymes involved in the metabolism of glucose already are maximally active in the absence of exogenous glucose administration (12), it seemed perhaps likely that administration of glucose would act to reverse a reduction in available glucose caused by increased demand rather than to elevate the baseline extracellular concentration.Previous work has shown that the level of glucose in the brain's extracellular fluid (ECF) increases in line with increases in blood glucose (13)(14)(15)(16) and that the level of glucose in the ECF is lower than that predicted by traditional models (17,18). However, such findings do not address the question of whether provision of glucose to the brain is always sufficient to meet demand. To investigate this issue, we measured the levels of glucose in the hippocampus of freely moving rats before, during, and after tests of spontaneous alternation, a task requiring spatial working memory and which is sensitive to lesions and drug manipulations of the hippocampus (refs. 19-28; for a review of the underlying behavioral significance of performance in this task, see ref. 29).To determine further the effects of variation in cognitive demand on ECF glucose, two mazes of differing cognitive demand were used. We also assessed the effects on both perfor...