The effect of chronic administration of glycyl-glutamine on depression like behavior in chronic mild stress; mediation of serotonergic and glutamatergic neurotransmitter systems in the effect

Depression is a common disorder all around the World. It affects more than 400 million people. Serious side effects, long treatment periods and a group of patients who do not respond with 40% of the drugs used today for the treatment of depression, leads to the need for more innovative pharmacological agents with different mechanisms of action. Glycyl-Glutamine (Gly-Gln) dipeptite is one of the major end products of hydrolysis of B-endorphine 1-31. In the previous studies it was shown that administration of Gly-Gln can inhibit the cardiovascular depression caused by morphine; and also alleviate the respiratory depression caused by morphine and also inhibit conditioned place preference induced by morphine, attenuate the development of morphine dependence and tolerance and abolish the withdrawal symptoms and also increase brain serotonin levels. To mimic the possible effects of Gly-Gln on chronic depression, a chronic mild stress model was applied to male Sprague-Dawley rats weighing 250-300 grams, using a different stressor every day for 4 weeks. Animals were divided into 3 groups as control, stress and Gly-Gln group. The stress levels of the animals and the effects of Gly-Gln on these levels were behaviorally evaluated using the splash test, marble burying test, the sucrose preference test, and the elevated plus maze test, while the neurobiological effects were evaluated by measuring serotonin in the hippocampus, glutamate in the prefrontal cortex, and Brain-drived neurotrophic factor (BDNF) in the plasma. Considering the results of behavioral studies, it was shown that Gly-Gln given chronically by the intracerebroventricular (icv) route significantly reduced depression- like behaviors without any negative effect on locomotor activity. In the neurochemistry stage of the study, it is also shown that Gly-Gln increases the serotonin impairment induced by stress, reduces the elevated levels of glutamate and increases BDNF levels which is highly important for neurogenesis, in the tissues of hippocampus and prefrontal cortex. As a result, it has been shown that Gly-Gln has a very effective antidepressant activity on depression-like behaviors in animals subjected to chronic stress. Further studies with Gly-Gln will shed light on the still unknown pathophysiology of depression. Keywords: depression, chronic stress, Gly-Gln