Effects of metformin on behavioral alterations produced by chronic sucrose consumption in male rats

Excessive consumption of sugary drinks negatively impacts the developing brain, producing long-lasting behavioral and metabolic disorders. Here, we study whether treatment with the antihyperglycemic agent metformin prevents some of the anxiety and memory alterations produced by chronic sucrose consumption. Male Sprague-Dawley rats had unrestricted access to water (control group) and a bottle containing a 10% sucrose solution (sucrose group, SUC) for 35 days. In parallel, a group of animals from SUC received metformin (25 mg/kg or 50 mg/kg, orally; MET 25 and MET 50 groups, respectively). After 2 weeks of metformin treatment, the animals weighed less than controls. SUC and MET 50 groups compensated for the caloric intake from the sugary solution by consuming less chow. In contrast, total energy intake in MET 25 was higher than the rest of the groups, but they still weighed less than control and SUC groups, suggesting that at this concentration, metformin delays body growth. The animals were then tested for the open field (OF), elevated plus maze (EPM) and novel object location (NOL) tests. In the OF, SUC animals spent more time in the central zone of the arena, evidenced by an increased number of entries and the distance traveled there. In the EPM, SUC animals spent more time in the open arms and less time in the central square. Metformin treatment prevented the decreased anxiety observed in SUC animals in the OF and EPM. In the NOL test, SUC animals showed less interest in novelty and metformin treatment did not improve this alteration. The preference for open spaces in the OF and EPM were associated with increased serum triglycerides (TG) and malondialdehyde levels in the medial prefrontal cortex (mPFC) and the hippocampus (HIP), while poor memory performance was associated with high basal blood glucose levels. In conclusion, the decreased anxiety-like behavior produced by chronic sucrose consumption was prevented by metformin treatment, through a mechanism that probably involves normalization of TG levels and decreased oxidative stress in mPFC and HIP. Chronic sucrose consumption during youth increases fasting blood glucose, triglycerides, and fructosamine levels and glucose intolerance. It also decreases anxiety-like behavior toward open spaces and produces memory deficits in male rats. Treatment with metformin prevents some of these alterations (pink panels on the left): it normalizes triglyceride levels, improves glucose tolerance, and decreases lipid peroxidation (MDA) in the brain. It also normalizes anxiety-like behaviors to control levels. On the contrary, treatment with metformin fails to normalize fasting blood glucose or fructosamine levels; or improve memory deficits (lilac panels on the right). Elevated levels of triglycerides and MDA are associated with an altered anxiety-related response, whereas hyperglycemia is associated with poor memory performance.image