Low-down on how Prozac knocks depression on the head

Scientists have discovered part of the process through which antidepressants boost mood. Writing in the journal Neuron, University of Paris-Sud scientist Denis David and his colleagues explain how they first made mice depressed by chronically administering doses of cortisol, a stress hormone, and then treated the animals with the depression-drug Prozac (fluoxetine). The scientists assessed how the animals' approached a series of tasks both while they were depressed and then after antidepressant treatment. The tests included measuring the animals' eagerness to walk across open spaces, their appetites and how well they groomed themselves.

In all cases the animals' performances improved with antidepressant therapy to resemble that of control mice. Then, to find out how the effect was being achieved the team studied the animals' brains. They found that the activities of three genes were significantly impacted by depression and fluoextine treatment: The genes were beta-arrestin-1, beta-arrestin-2 and Gi-alpha-2, all of which were switched off in the depressed animals in a part of the brain called the hypothalamus - which, amongst other processes, also controls mood, sleep and appetite.

These genes were switched back on by the antidepressant treatment. Mice engineered to lack one of these genes - beta-arrestin-2 - subsequently failed to respond in the behavioural tasks to fluoxetine treatment, indicating that fluoextine exerts its effects through this gene. Importantly, however, fluoextine also boosts the production of new nerve cells in a brain region called the hippocampus, and when the scientists blocked this process they found that the depressed mice failed to improve in some of the behavioural tasks. This suggests that there are two mechanisms through which drugs like Prozac exert their effects: one, by activating certain genes, and two, by provoking the birth of new nerve cells that in some way help to patch up the neurological problem that is triggering low mood.

Teasing the two effects apart is the next challenge. "The big unanswered question is whether future drugs that directly stimulate neurogenesis will be as effective as antidepressants or will only ameliorate cognitive defects," says co-author Rene Hen.