Scientists have used hippocampal stem cells to demonstrate a key role for the glucocorticoid receptor in the process by which antidepressants stimulate neurogenesis. Initial studies on the stem cells using the SSRI antidepressant sertraline, were subsequently verified in additional experiments with the tricyclic antidepressants amitriptyline and clomipramine.
The researchers, from the Institute of Psychiatry, Kings College, report their findings in Molecular Psychiatry. The paper is titled “Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor.”
The effects of antidepressants on hippocampal neurogenesis have been demonstrated for different, chemically unrelated classes of antidepressants, suggesting that a common molecular mechanism may underlie their neurogenic potential, reports Christoph Anacker, Ph.D., and colleagues. Identifying the mechanism could thus potentially lead to the discovery of new targets that could counteract the neurobiological disturbances of depression.
The Institute of Psychiatry researchers’ work was designed to follow on from recent studies suggesting that glucocorticoids are involved in the neurogenic action of antidepressants, and previous work at Dr. Anacker’s lab and by other teams demonstrating that antidepressants directly regulate the function of the glucocorticoid receptor. The team built on these observations by studying the effects of antidepressants on hipoccampal stem cells in vitro in order to separate the direct effects of the drugs on progenitor cells from any potential indirect effects, which would be present in an in vivo model.
They found that treating the stem cells with sertraline for 3–10 days increased neuronal differentiation via a glucocorticoid receptor-dependent mechanism involving PDE4/PKA signaling. Essentially, drug-related activation of the glucocorticoid receptor prompted the switching on of genes that converted progenitor cells into adult brain cells. Conversely, treating the cells with stress hormones had exactly the opposite effect.
“For the first time in a clinically relevant model, we were able to show that antidepressants produce more stem cells and also accelerate their development into adult brain cells,” Dr. Anacker claims. “We will now be able to use this novel stem cell system to model psychiatric illnesses in the laboratory, test new compounds, and develop much more effective targeted antidepressant drugs.”