The content of "energy-rich" phosphates was markedly decreased in rat cerebral cortex after 20 min of severe hypoglycemia, followed by partial restitution during the recovery period. The adenine nucleotide pool remained reduced even if the energy charge returned to normal. During hypoglycemia the non-glucose endogenous substrates were provided by glycolytic intermediates, by Krebs' cycle intermediates and by related amino acids. Other substrates for brain oxidation were provided by the breakdown of phospholipids and fatty acids. After a 20 min period of post-hypoglycemic recovery, partial restoration of carbohydrates and amino acids occurred, the amino acid pool size being still reduced. The alterations in phospholipids and fatty acids persisted, while there was a tendency towards normalization of the free fatty acid cerebral content. During the post-hypoglycemic recovery, treatment with some specific metabolic modulators (i.e., uridine, L-acetylcarnitine, hopantenate, 6-amino-nicotinamide) suggests the possibility of an alternative cerebral substrate utilization due to the modulation of the cerebral biochemical machinery. Thus, increased carbohydrate utilization by hopantenate was consistent with decreased lipid breakdown, while increased carbohydrate utilization by uridine was concomitant with decreased amino acid degradation. On the other hand, decreased cerebral carbohydrate utilization by 6-aminonicotinamide was concomitant with increased lipid and amino acid breakdown. Furthermore, the increased loss of cerebral phospholipids and fatty acids by L-acetylcarnitine occurred in the presence of a large glucose availability and was concomitant with an extensive reduction on cerebral glycolytic flux.