Using optical recording methods in the rat lateral septal nucleus (LSN) slice, we examined the question of whether antecedent hypoglycemia protects neurons from the adverse effects of subsequent hypoglycemic stimuli. The first exposure of LSN neurons to glucose deprivation for 15 min produced a marked depression of neuronal activity. The neuronal activity recovered by reapplication of glucose to the neurons. In neurons previously exposed to glucose deprivation, subsequent applications of glucose-free artificial cerebrospinal fluid (ACSF) produced only weak depression of the neuronal activity. The contribution of monocarboxylate transporters to this adaptation of neuronal activity to repeated glucose deprivation was examined in LSN neurons. alpha-Cyano-4-hydroxycinnamate (4-CIN, 100 microM), an inhibitor of the monocarboxylate transporters, did not significantly affect the depression of the neuronal activity induced by the first glucose deprivation. However, in the presence of 4-CIN (100 microM), a second glucose deprivation produced a typical depression of the neuronal activity, indicating that 4-CIN had nullified the adaptation of neuronal activity to a second glucose deprivation. Cytochalasin B (CCB, 20 microM), an inhibitor of glucose transporters, depressed the neuronal activity in the presence of 11 mM glucose. Pyruvate (11 mM) partially restored the neuronal activity depressed by pretreatment with CCB (20 microM) for 30-40 min. These results suggest that antecedent glucose deprivation stimulates monocarboxylate-transporters to supply energy substrates to LSN neurons, thus protecting the neurons against subsequent glucose deprivation. .