Previous work in our laboratory has shown that neural trauma results in a disparity between oxidative and glycolytic rates. In non-neural tissue, glycolysis and oxidative phosphorylation have been shown to work independently of one another, a phenomenon known as “energy compartmentalization”. We believe that functional compartmentalization of energy production may also occur in the brain with glycolysis providing energy for membrane bound ionic pumps. Spreading depression, induced in rodent brain by topical KCl application, results in K⁺ shifts. The restoration of K⁺ gradients is accomplished by energy dependent Na⁺-K⁺ pumps. If these pumps depend upon glycolysis, blocking glycolysis should prevent reconstitution of normal [K⁺]_c levels. The present series of experiments were designed to suggest that energy compartmentalization may also exist in brain, and that glycolytic energy production is preferentially used by Na⁺-K⁺ pumps to maintain normal ionic homeostasis by observing the dynamics of spreading depression induced K⁺ shifts before and after glycolytic blockade. Spreading depression was associated with increased K⁺ (48.6 ± 16.6 mM over control) that normalized within 2.9 ± 0.3 minutes. Following superfusion with a glycolytic blocking agent, spreading depression produced similar increases in [K⁺]_c (40.6 ± 12.0 mM over control) but time for reconstitution of the normal [K⁺]_c was 400% longer than controls (2.9 ± 0.3 to 14.9 ± 2.1 minutes, P < 0.001). Time required for recovery of EEG was identical pre- and post-blockade. We believe these data suggest that energy compartmentalization may exist in neural tissue and that glycolytic pathways of energy production are functionally tied to membrane Na⁺-K⁺ pumps. Although lactate, a by-product of glycolysis, has traditionally been considered an indication of ischemia or mitochondrial damage, we suggest that it may also reflect glycolytic energy production required to re-establish disturbed trans-membrane ionic gradients.