This Is a Mouse's Brain on Prozac

How, exactly, do antidepressant drugs like Prozac affect the brain?
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How, exactly, do antidepressant drugs like Prozac affect the brain?

A new experimental mouse model of depression and anxiety — the first to allow simultaneous analysis of the different effects of antidepressant drugs, like Prozac, on the same animal — could lead to the development of better treatments for those disorders, according to a major new study published in the journal Neuron.

Until now, the exact molecular influences of selective serotonin reuptake inhibitors (also known as SSRIs) and other types of antidepressants have not been well understood.

"Recently, compelling work in rodents has suggested that SSRIs may stimulate changes in a brain region called the hippocampus as well as other brain structures," said study author Denis J. David of the University of Paris-Sud in a press release announcing the findings. "For example, anxiety/depression-like changes in behavior have been linked with a decrease in cell proliferation in the hippocampus, a change that is reversed by antidepressants."

David and his colleagues created a mouse model of depressive and anxiety disorders to investigate how antidepressants impact the brain. Previous studies have shown that long-term exposure to glucocorticoids - a class of steroid hormones - creates anxiety and a depressive-like state in rodents; high levels of glucocorticoids have also been linked with depression and anxiety in people. So the researchers developed a mice model of anxiety and depression based on high glucocorticoid levels that "offered an easy and reliable alternative to existing models," said David.

When the experimental mice received chronic antidepressant treatment, the behavioral dysfunctions and inhibition of hippocampal neurogenesis — or the proliferation of neurons in the brain — was reversed. When this process was prevented, the effectiveness of Prozac lessened on some of the rodents' behavior. The researchers were then able to pinpoint certain genes whose expression in another section of the brain, the hypothalamus, was normalized after taking Prozac.

This finding suggests that both neurogenesis-dependent and -independent mechanisms form the basis of antidepressant effects, which could, in turn, provide a target for treatment.

"The big unanswered question is whether future drugs that directly stimulate neurogenesis will be as effective as popular antidepressants or will only ameliorate cognitive deficits," said another of the study's authors, Rene Hen from Columbia University.

"To begin to answer this question we are using our paradigm to test a series of compounds that may stimulate neurogenesis more directly or compounds that directly target the hypothalamus. Ultimately, it is the success of these new compounds in the clinic that will establish the predictive value of the biomarkers we have identified in this report."

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