Blocking the formation of neurons in mouse brains blocks the behavioral effects of antidepressants, supporting the theory that the drugs spur brain cell growth and helping explain why they take a few weeks to work.
“If antidepressants work by stimulating the production of new neurons, there’s a built-in delay,” says Rene Hen, a researcher from New York’s Columbia University. “Stem cells must divide, differentiate, migrate and establish connections with post-synaptic targets — a process that takes a few weeks.”
Studies have shown that chronic stress, anxiety and depression are linked to a loss of hippocampal neurons and that neuron growth is promoted by antidepressants.
But the details of how this works are unclear, so Hen and colleagues sought to demonstrate a causal relationship between antidepressants, newly generated neurons and relief from depression.
To do this, they created a strain of “knockout” mice that lacked the gene for a key subtype of receptor for the neurotransmitter serotonin.
As adults, the mice showed traits related to anxiety, such as a reluctance to begin eating in a new environment.
The researchers then selectively targeted the hippocampus of these mice and a normal group with x-rays to kill proliferating neurons and reduce neuron growth by 85%.
Both groups were then treated with the antidepressant fluoxetine, which is part of a class of antidepressants called selective serotonin reuptake inhibitors, or SSRIs, that is widely used to treat anxiety and depression.
Fluoxetine had no effect on the anxious knockout mice, but it altered behavior and doubled the number of neurons in the hippocampus of the normal mice.
A tricyclic antidepressant called imipramine that acts on a neurotransmitter called norepinephrine rather than serotonin worked on both groups of mice.
With a clearer understanding of how antidepressants work, the researchers hope to pursue new avenues for treating anxiety and depression.