Preclinical approaches to examine novel concepts of the pathophysiology of depressive disorders: Lessons learned from tree shrews

Recent studies have provided evidence that mood disorders such as major depression not only have a neurochemical basis but are also associated with alterations in neuronal and glial Structures. Anti depressants may act by restoring structure as well as function of neural networks meaning that they may, as a fundamental principle, affect neural Plasticity underlying normal brain functioning. To examine this novel concept of the pathophysiology of depression and antidepressant medication, we have carried Out I series of experiments using the social stress paradigm in tree shrews, an animal model with a high validity for the pathophysiology of major depression. We found that 1 month of stress reduced the proliferation rate of newly born neurons in the dentate gyrus and decreased hippocampal volume. Notably, the suppressive effects of social conflict stress on hippocampal structure could be counteracted by treatments with different antidepressants such as clomipramine, tianeptine, and the selective NK1 receptor antagonists L-760735. In addition, the stress-induced decrease in number of parvalbumin-containing cells in the hippocampal formation, presumably GABAergic interneurons, was prevented by concomitant treatment with fluoxetine. These studies show that different classes of antidepressants can reverse the structural alterations of the hippocampal formation induced by stress.