Andrew Rennekamp, PhD
Andrew Rennekamp, PhD, is using the behavior of zebrafish to investigate new antipsychotic compounds.
Zebrafish larvae

What can an experiment involving fish larvae and a strobe light tell us about mental illness?

As it turns out, quite a lot.

A team of researchers at Massachusetts General Hospital recently used the larvae of zebrafish in two behavior-based experiments to learn more about the brain mechanisms behind psychosis and threat response.

The results are providing better insights on what triggers our reaction to perceived danger and may help to identify new treatments for a variety of mental disorders, such as psychosis, schizophrenia, post-traumatic stress disorder (PTSD) and depression.

The research could also address a significant need for new antipsychotic medications, as many of the medications currently available to patients have serious side effects.

In a recent interview, Andrew Rennekamp, PhD, explained that mental health drug discovery has historically taken a target-based approach, where scientists identify a specific receptor or protein in the brain and then try to find chemicals that will act on that one target.

The approach developed by Dr. Rennekamp and Randall Peterson, PhD, differs by using the behavior patterns of zebrafish as an indication of the drug’s potential effectiveness instead.

Rennekamp believes a behavior-based approach to drug development is critical in mental health, where clinical trials for drugs that impact the central nervous system (CNS) are twice as likely to fail as non-CNS drugs.

“We are trying to find chemicals in a more holistic way, where you have all the targets in an experiment rather than just one," Rennekamp explains. "We need this approach for complex conditions like schizophrenia, where you have a whole system in the brain that is functioning abnormally.”

Zebrafish illustration

In the first of their two experiments, Rennekamp and Peterson took advantage of the natural tendency of zebrafish larvae to freeze in response to the perceived threat of a rapidly flickering strobe light.

Although threat response is frequently referred to as “fight or flight,” there are actually three different threat responses that most animals (including humans) exhibit when confronting a dangerous situation—fight, flight or freeze.

The freeze response is essentially a paralyzed state that allows the individual to disassociate from the impending danger. This behavior is best displayed by a deer that freezes when confronted with the headlights of an oncoming car.

While coming to a standstill in front of an approaching automobile is arguably not in the deer’s best interests, freezing can be helpful in some situations for animals that are trying to hide from motion-sensitive predators.

By identifying this freeze behavior as the zebrafish larvae’s default response to exposure to the strobe light, the researchers were able to test a variety of chemical compounds to see if any of them changed that response.

Through trial and error, the team found that compounds that target the signal one (σ1) receptor in the brain were able to change the behavioral response from freezing to flight. They named these compounds the “Finazines” in recognition of the role the fish played in the discovery process.

Understanding what causes the switch between freezing and escape behavior could help in treating issues such as PTSD, where the fight or flight response may be sent into overdrive by trauma, or in motivational disorders such as depression, where the patient may be unable to act due to the paralyzing effect of severely depressive thoughts, Rennekamp explains.

The team is now working on changes to the chemical structure of the Finazines in order to optimize the biological effectiveness of the compounds. They will also conduct more tests to better understand how the compounds interact with various organs, tissues and enzymes in the human body.

In a second experiment, Rennekamp and Peterson tested the effects that a series of known antipsychotic drugs had on 10 different behavioral traits that could be identified in zebrafish larvae.

They found that the antipsychotics created a specific behavioral signature in the larvae that was different from the way the larvae behaved when treated with a known stimulant or antidepressant.

Identifying this antipsychotic-specific behavior pattern now makes it possible for the team to test thousands of new compounds that aren’t yet drugs to see if they can find other compounds that produce the same response, Rennekamp explains.

Those compounds could then be tested further to see if there is the potential to turn them into new antipsychotic medications.

Rennekamp believes that these behavior-based models of drug development work well in harmony with other methods of discovery, including the previously mentioned target-based approaches.

Rather than being at odds with each other, he views the approaches as complementary. “There’s no reason we can’t do them all.”

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