Agomelatine-induced changes in monoamine levels of the diabetic brain: treatment of diabetes-induced depressive behavior

摘要

Objective: Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia, which is caused by failure in insulin secretion and/or action that triggers various acute and chronic complications. The central nervous system complications of diabetes are known as “diabetic encephalopathy”. Emotional disorders are more frequent in diabetic patients with respect to the general population. Changes in the central monoamine levels are accepted as the mechanisms responsible for the mentioned psychiatric disorders. Based on this knowledge, we investigated the effect of agomelatine treatment on diabetes-induced behavioral changes and alteration of monoamine levels in the brain. Method: Sprague-Dawley rats of the same age (weight: 250-350 g) were used. Total protocol was started with the induction of diabetes by a single intravenous administration of streptozotocin at 50 mg/kg dose; subsequently, agomelatine was administered at the fourth week, and further behavioral and analytical experiments were performed at the end of the sixth week. The experimental protocol was approved by the Anadolu University Animal Experiments Local Ethics Committee.; The effect of two weeks’ agomelatine (40 mg/kg) administration on depressive behavior of diabetic rats was investigated with modified forced swimming test (MFST). The count of swimming, climbing and immobility behaviors over a 5 sec interval during 5 min was recorded for this purpose. ; Following the behavioral tests, rats were sacrificed and the brains were removed. Following a conventional homogenization process, the resulting supernatant was removed and used for further analytical studies. Determination of serotonin, noradrenaline and dopamine levels was performed by liquid chromatography. Results: In MFST, immobility counts of diabetic animals were found to be increased at week 4, whereas the number of climbing and swimming behaviors was decreased. Agomelatine treatment reduced the increased immobility of diabetic animals with a significant increase in the number of climbing behavior, with respect to the untreated diabetic rats. Chromatographic analyses proved that serotonin, noradrenalin and dopamine levels were decreased in brain homogenates of diabetic rats with respect to normoglycemic animals. In addition, when compared to the untreated diabetic animals, it was observed that agomelatine treatment increased central noradrenaline and dopamine levels of diabetic rats significantly. However, serotonin levels were not change in the agomelatine treated group. Conclusion: Findings of this study indicate that agomelatine administration restores depression-like behaviors of diabetic rats to normal levels. Moreover, increased noradrenaline levels in the brain seem to be responsible for the beneficial effect of agomelatine on diabetes-induced depression-like behavior.