Acute hypoglycemia causes depressive-like behaviors in mice

Reports in humans advocate a link between hypoglycemia and altered mood. Such observations, however, have not been mechanistically explored. Here we examined depressive-like behaviors in mice resulting from acute hypoglycemia. Mice were fasted for 12 hours and then administered intraperitoneal insulin to induce a blood glucose nadir of 50 mg/dL at 0.75 hour after injection that by 2 hours postinjection had returned to normal. The behaviors of locomotion, forced swim, saccharin preference, and novel object recognition were subsequently examined. Mice made hypoglycemic showed depressive-like behaviors 24 hours after resolution of hypoglycemia as evidenced by increased immobility in the forced swim test (FST) and reduced saccharin preference. Movement and memory were not impacted by hypoglycemia 24 hours after its resolution. By 48 hours posthypoglycemia, depressive-like behaviors resolved. In contrast, neither peripheral insulin administration without resultant hypoglycemia nor intracerebroventricular insulin administration altered performance in the FST. The antidepressants fluoxetine and desipramine prevented hypoglycemia-induced immobility in the FST, as did the antiadrenergic agents phentolamine, metoprolol, and butoxamine. Epinephrine and norepinephrine administration caused increased immobility in the FST at 24 hours postadministration that subsequently resolved by 48 hours. These data indicate that, in mice, acute hypoglycemia through adrenergic pathways caused depressive-like behaviors that exist well beyond the resolution of hypoglycemia.