Researchers at the University of Zurich and Harvard University have developed a new strategy in the search for psychoactive drugs. By analyzing the behavior of larval zebrafish , they can filter out substances with unwanted side effects right from the start.

Many drugs that take effect in the brain have unwanted side effects. The appetite suppressant Rimonabant , for example, can cause anxiety, depression or even suicidal thoughts, which is why it is taken from the market.

"Brain structures are highly complex, which raises the question of whether it is possible for a drug to trigger only one very  specific behavior ," says Josua Jordi, a researcher at the UZH Institute of Veterinary Physiology To answer this question, I have joined forces with US researchers to develop a novel testing system for psychoactive substances.

Using zebrafish larvae as live measuring tools

Unlike previous biochemical tests, the new testing system uses the larvae of zebrafish , which are about four millimeters long. The biology of these tropical fishes well characterized, and they can be bred quickly in large quantities. 

The researchers established an automated measuring process so that they could analyze the behavior of several thousand larvae at the same time. This involved feeding fluorescent paramecia to the fish  in order to quantify their feeding behavior-the more fluorescence there is in the larva's stomach, the bigger their appetite. 

The researchers also developed similar methods for a number of other behaviors, including the fish's reaction to light and sound, or simply learning tasks  Experiments with known active substances confirmed that the system works. 

For example, nicotine was found to reduce the larva's appetite while increasing their activity. This is in line with the effects nicotine has on many animals, as well as humans.

In their large-scale experiment, the scientists searched for appetite modulators and determined the effects of more than 10,000 small molecules on the behavior of larval zebrafish

They found more than 500 substances that either increased or suppressed the appetite of the larvae. However, only about half of these had the specific effect of only modulating the animals' appetite; the other half resulted in additional behavioral changes. 

"By analyzing several behaviors in parallel, we were able to filter out many substances with non-specific effects from the beginning," says Josua Jordi, first author of the study. "We were very happy to see that right away, our approach had the desired effect."

Same effect in mice

Next, the researchers investigated the biological mechanisms of 22 of the most promising substances. They found that some of these substances had an effect on the activity of key neurotransmitters  in the brain, such as serotonin or histamine, which is precisely how many of the existing appetite modulators unfold their effects. 

"The crucial finding, however, was that it did not interfere with any of these known systems," says Florian Engert, last author of the study and professor at Harvard University. This points towards new molecular mechanisms that regulate appetite .