Regulation of insulin receptor phosphorylation in the brains of prenatally stressed rats: New insight into the benefits of antidepressant drug treatment

A growing body of evidence supports the involvement of disturbances in the brain insulin pathway in the pathogenesis of depression. On the other hand, data concerning the impact of antidepressant drug therapy on brain insulin signaling remain scare and insufficient. We determinated the influence of chronic treatment with antidepressant drugs (imipramine, fluoxetine and tianeptine) on the insulin signaling pathway of the brain of adult prenatally stressed rats. 3-month-old prenatally stressed and control rats were treated for 21 days with imipramine, fluoxetine or tianeptine (10 mg/kg/day i.p.).The impact of chronic antidepressant administration was examined in forced swim test. In the frontal cortex and hippocampus, the mRNA and protein expression of insulin, insulin receptor, insulin receptor substrates (IRS-1,IRS-2) and adaptor proteins (Shc1, Grb2) before and after drugs administration were measured.Rats exposed prenatally to stressful stimuli displayed depressive-like disturbances, which were attenuated by antidepressant drug administration. We did not reveal the impact of prenatal stress or antidepressant treatment on insulin and the insulin receptor expression in the examined structures. We revealed that diminished insulin receptor phosphorylation evoked by the prenatal stress procedure was attenuated by drugs treatment. We demonstrated that the favorable effect of antidepressans on insulin receptor phosphorylation in the frontal cortex was mainly related with the normalization of serine312 and tyrosine IRS-1 phosphorylation, while in the hippocampus, it was related with the adaptor proteins Shc1/Grb2. It can be suggested that the behavioral effectiveness of antidepressant drug therapy may be related with the beneficial impact of antidepressant on insulin receptor phosphorylation pathways.