Scientists Deep Dive into Depression Treatments

Major depressive disorder is a widespread mental illness. The National Institute for Mental Health reports an estimated 7.1% of Americans have experienced at least one major depressive episode. To better understand this malady, research on a commonly found aquarium species, zebrafish (Danio rerio), is now taking place to model mental disorders, such as depression. 

Although zebrafish have only recently been introduced to model mood disorders, these fish have a long history with scientific experimentation. Zebrafish are often used for medical research and drug development because their relatively rapid maturation rate and predictable sizing make them ideal models. These features have been noted by Dr. Angelo Piato at the Federal University of Rio Grande do Sul in Brazil, who has been studying zebrafish for more than a decade. 

Dr. Piato, who previously studied rodents, started working with zebrafish during his postdoctoral fellowship, when he helped create a new chronic stress protocol using these animals. 

“When we submit rodents to stress or humans to stress, chronic stress, the outcomes are basically the same [as in zebrafish],” Dr. Piato says. This observation has been useful in his more recent work, where he has been testing new drugs on psychiatric diseases that often are caused by stress, such as major depression. 

In a 2018 study, Dr. Piato and his colleagues investigated acetyl-L-carnitine (ALCAR), a natural chemical known for its anti-stress and anxiolytic (anti-anxiety) abilities. Dr. Piato and his team housed 240 adult zebrafish for fourteen days before exposing them to ALCAR for ten minutes at different concentrations (0.1, 1.0 and 10.0 mg/L). The groups were then subjected to one of three tests: response to a novel tank, a light and dark test, or an acute stress test followed by the novel tank test. All these tests are common protocols for measuring anxiety and stress-related behaviors in zebrafish. 

When ALCAR enters the zebrafish brain, it directly impacts the cholinergic system which is, in part, responsible for regulating emotions and mood. It has a neuroprotective effect on some neurons, which may minimize the effects of stress. ALCAR supports dopamine production, a brain chemical which generates feelings of happiness and reward. ALCAR’s impacts on zebrafish may have also decreased stress and anxiety in the animals. Dr. Piato’s research also notes how ALCAR improves mitochondrial function. Mitochondrial dysregulation is commonly present in psychiatric disorders. 

Other scientists are also studying fish as models for psychiatric conditions. Species such as the common goldfish (Carassius auratus) and rainbow trout (Oncorhynchus mykiss) have also been used in stress-related settings and may similarly contribute to our understanding of complex mental disorders. 

Dr. Piato cautions that a constraint among animal models is measuring positive behavior. For zebrafish, one of the main constraints is that it is difficult to observe behaviors related to anhedonia (inability to feel pleasure). 

“We have a fish and we are mammals. So, we need to consider the difference,” notes Dr. Piato. 

In the meantime, Dr. Piato wishes to continue his research with zebrafish, hoping to develop new research protocols and also study the impacts of other psychiatric diseases. 

Because depression rates are increasing among youth ages 12 to 17, rising from 8.7% in 2005 to 12.7% in 2015, clinical research on this and related topics is expected to grow. Scientists are also hopeful that research in zebrafish and other species will lead to new and better human therapies.