A new experimental mouse model that uses glucocorticoids, a class of steroid hormone, to induce anxiety and depression in mice has shown that the effects of antidepressants are mediated through both neurogenesis-dependent and -independent mechanisms.
Neuroscientist René Hen and colleagues from Columbia University, along with Denis David and colleagues from the University of Paris-Sud, first tested the model by administering corticosterone to mice and then treating them with different antidepressants, including fluoxetine (Prozac). Treatment with the antidepressants reversed behavioral dysfunctions induced by the hormone, suggesting that corticosterone exposure is a reliable and simple method to model a state of anxiety/depression in mice.
The researchers then investigated potential ways in which fluoxetine worked in the mice, looking in particular at treatment effects on neurogenesis in the hippocampus. Previous research has suggested that hippocampal neurogenesis is linked to antidepressant action.
Corticosterone decreased neurogenesis, but the effect was completely reversed by three weeks of fluoxetine treatment. When neurogenesis was completely inhibited in the hippocampus by irradiation before corticosterone exposure, the positive treatment effect of fluoxetine was blocked in some, but not all, of the behavioral tests. This suggests that some aspects of the treatment response to fluoxetine are dependent on neurogenesis, while others are independent of it.
In the research, published May 28 in Neuron, investigators also found that expression of the gene beta-arrestin 2 in the hypothalamus, which was decreased by corticosterone, was normalized by fluoxetine. Mice that were missing this gene had a reduced response to the antidepressant, indicating that beta-arrestin 2 is necessary for fluoxetine to work.
“We don’t know at present which of these effects are critical for the therapeutic results of these drugs in humans,” says Hen. “Now the question is, if you stimulate just one of the processes—the one we’re most interested in is neurogenesis—what is the behavioral impact?”
*A shorter version of this item appears in the print edition of BrainWork.