Depressed fish could help in the search for new drug treatments

Chronic stress can lead to depression and anxiety in humans. Scientists working with Herwig Baier, Director at the Max Planck Institute of Neurobiology in Martinsried, recently discovered a very similar link in fish. Normally, the stress hormone cortisol helps fish, as in humans, to regulate stress. Fish that lack the receptor for cortisol as a result of a genetic mutation exhibited a consistently high level of stress. They were unable to adapt to a new and unfamiliar situation. The fishes' behaviour returned to normal when an antidepressant was added to the water. These findings demonstrate a direct causal link between chronic stress and behavioural changes which resemble depression. The findings could also open the door to an effective search for new drugs to treat psychiatric disorders.

In stressful situations, the body releases hormones in order to ready itself for a fight or flight reaction. But it is equally important for the hormone level to return to normal after a certain time. If that does not happen, chronic stress can result, a condition that is linked to depression and anxiety, among other things. Whether stress is a trigger or merely a side effect of such affective disorders remains unclear.

The indication of a causal relationship between stress and depression comes from totally unexpected quarters. An international team led by Herwig Baierfrom the Max Planck Institute of Neurobiology in Martinsried and the University of California in San Francisco observed that zebrafish suffering from chronic stress as a result of a genetic mutation showed signs of depression in behavioural tests. The zebrafish is a popular model organism for biological and medical research. So far, however, it has not been an obvious research object for the study of psychiatric disorders. This may be about to change.

"These mutant fish behaved very strangely when we moved them to a new aquarium," reports Herwig Baier. All animals experience stress upon moving to an unfamiliar environment. Being separated from members of their own species places the fish under added pressure. Zebrafish initially act withdrawn in this situation and swim around very hesitantly in the first few minutes. But ultimately, curiosity prevails, and they begin to investigate their new tank. However, the fish with the mutation had a particularly strong reaction to the isolation: they sank to the bottom of the tank and stayed completely still. They took an exceptionally long time to get used to the new environment.

An analysis of these "lethargic" fish showed that they had an extremely elevated concentration of the stress hormones cortisol, CRH and ACTH. "We therefore postulated that these fish were suffering from chronic stress and were exhibiting certain aspects of depressive or perhaps hyper-anxious behaviour," says Baier. To put this assumption to the test, the scientists added the antidepressant fluoxetine (marketed under the trade name Prozac, among others) to the water. Shortly afterwards, the fish's behaviour returned to normal.

What was it that made these fish so different? The scientists uncovered a mutation in the glucocorticoid receptor, which is present in almost all of the body's cells and which binds the hormone cortisol. Normally, when cortisol is bound to this receptor it restricts the release of the stress hormones CRH and ACTH. It is this regulating mechanism that enables humans and many animal species to cope with stress. In the type of fish the scientists examined, however, the glucocorticoid receptor was unable to function, and so the level of stress hormones remained high.

"Although there are a whole range of drugs available for depression, no one yet knows what the relationship is between their effect and the stress hormones," explains Herwig Baier. "Our findings provide the first evidence of a possible connection." Understanding the molecular and neurobiological relationships between stress regulation and affective disorders is important in the search for new treatments and drugs. The scientists' discovery is therefore also of interest to the pharmaceutical industry, given that the zebrafish could turn out to be a good model organism for a large-scale screen for new drugs.