Effects And Underlying Mechanisms Of Phosphatidylinositol-linked D₁-like Receptor In The Major Depressive Disorders Of Mice

Part I Effects of phosphatidylinositol (PI)-linked D1-like receptor agonist on major depressive disorderAim:Depression is a group of syndromes characterized by notable and persistent mood disorders. Although current therapy improves depression, the symptoms fail to resolve completely in as many as half of cases. Remission rates are even worse for those who have failed initial medication trials. Thus, the antidepressants with higher efficacy and fewer side effects are needed. Growing evidence indicates a relationship between dopamine system and depression, and some dopamine receptor agonists have been proved to produce antidepressant effects.The dopamine receptor that activates the PLC/IP3pathway has been called the phosphatidylinositol (PI)-linked D1-like receptor (PI-D1receptor), a novel dopamine D1-like receptor. However, it remains unknown that whether activation of this receptor could modulate depression. We thus did a series of experiments to explore this hypothesis.Methods:Intraperitoneal injection, intracerebroventricular injection, forced swim test (FST), open field test, chronic social defeat stress (CSDS), sucrose preference test, social interaction test, double-labeling immunofluorescence and golgi silver staining were used in this section.Results:Behavioral experiments showed that activation of PI-D1receptor by SKF83959could produce robust antidepressant-like effect without affecting spontaneous locomotor activity, and this effect was associated with D1-like receptor activation but independent of D2-like receptor. Molecular biology techniques revealed that SKF83959treatment also counteract the deficiency of neurogenesis and dendrite spine density caused by CSDS. Conclusion:Chronic activation of PI-D1receptor by SKF83959treatment produces effective antidepressant efficacy in various animal models of depression. Part II The antidepressive mechanism of phosphatidylinositol (PI)-linked D1-like receptor agonist SKF83959Aim:The pathophysiology of depression is complex and involves many moleculars and proteins, like BDNF cascade, serotonergic system and HPA system. Having demonstrated the antidepressant effects of SKF83959, we then investigated the antidepressive mechanism of SKF83959by using various methods.Methods:Intraperitoneal injection, intracerebroventricular injection, forced swim test (FST), open field test, chronic social defeat stress (CSDS), sucrose preference test, social interaction test, western blotting, RT-PCR, radioimmunoassay test, double-labeling immunofluorescence and golgi silver staining were used in this section.Results:Molecular biology techniques revealed that SKF83959treatment restore the stress-induced decrease in hippocampal BDNF-CREB signaling pathway, and produce no effects on hippocampal NGF, NT3, and NT4. We also proved that the PI-D1receptor-mediated effect is selective to hippocampus. By using various inhibitors, we further demonstrated that SKF83959treatment produced antidepressant-like effects through PLC/IP3signaling pathway and BDNF-TrkB signaling cascade, and serotonin depletion does not alter the effects of SKF83959. Furthermore, stress-evoked corticosterone responses are normal in the SKF83959-treated mice, suggesting that activation of PI-D1receptor has no influence on the dysfunction of hypothalamus-pituitary-adrenal (HPA) axis.Conclusion:Chronic SKF83959treatment produces effective antidepressant efficacy through PLC/IP3pathway, and by modulating the function of hippocampal BDNF system and neurogenesis.