Caffeine: remedy or poison?

Studies presented at a worldwide congress on brain research suggest that caffeine may prevent depression in adults but could be a risk factor for epilepsy during fetal development.

By Karina Toledo, in Rio de Janeiro

Agência FAPESP – The difference between remedy and poison often lies in the dose, according to an old saying. In the case of caffeine, it may also depend on the age of the user. Whereas in adult individuals, the substance appears to protect the brain from damage caused by stress and may help stave off depression, its use by a pregnant woman may hinder fetal brain development and increase the newborn’s susceptibility to diseases such as epilepsy.

Findings, such as these from studies using mice, were presented during the Ninth World Congress of the International Brain Research Organization (IBRO 2015), held in Rio de Janeiro, Brazil, on July 7-11.

One such research project has been ongoing for 15 years, with Rodrigo Cunha at the University of Coimbra, Portugal, as principal investigator. Its aim is to find out whether and to what extent caffeine can prevent the development of depression, a disease that affects some 15% of the world population and is a leading cause of incapacity according to the World Health Organization (WHO).

The research group, which also includes collaborators in Germany, the United States and Brazil, subjected two groups of mice to chronic unpredictable stress for three weeks. One of the groups began receiving caffeine in its drinking water two weeks before the experiment. Tests showed that the concentration of caffeine in the animals’ blood was equivalent to that of a human adult who consumes two to three cups of coffee per day.

“We tried to reproduce in an animal model what human beings feel at those times in life when everything goes wrong. Your car breaks down, you lose your job, you end an affair, or you find out a friend has cancer. The whole world is turned upside down, and that feeling often gives rise to a depressive disorder,” Cunha told Agência FAPESP.

In the animal model, stress was induced by actions such as shaking the mouse’s cage for a few seconds, depriving the mice of food temporarily, giving them cold baths or tapping their paws.

A series of biochemical, neurochemical, electrophysiological and behavioral tests were performed after the experiment to evaluate factors considered to be indicators of depression in both groups.

“Animals can’t tell us if they’re depressed, so we evaluated the behavior of these mice with a series of standard tests,” Cunha said.

One of the tests consists of forcing the animals to swim for a few minutes. Under normal conditions, mice try to escape at all costs. A depressed mouse, however, will quickly give up and try to float. “It’s as if the animal decided to wait for life to solve its problems,” Cunha said.

Depressed mice are also less interested in making an effort to reach a sugary drink (loss of pleasure or anhedonia), may display memory deficits, and tend to be more withdrawn at times of social interaction.

The researchers also measured levels of corticosteroids – the animal equivalent of the stress hormone cortisol – and levels of certain proteins that are usually altered in patients with depression, as well as neural circuit information flows.

“We found that information continues to flow normally. What changes in depression is the meaning given to incoming information,” Cunha said. “The ability to adapt rapidly to external stimuli appears to be lost in depressed animals.”

From the test results, the researchers concluded that the group treated with caffeine displayed significantly fewer symptoms of depression than the control group. The next step was to characterize the molecular target responsible for this observed effect.

“Our previous studies had already shown that caffeine binds to the A2A adenosine receptor in cells, and we wanted to demonstrate that we could interfere in the results by manipulating this receptor pharmacologically or genetically,” Cunha said.

The A2A receptor is abundant in neurons and binds to adenosine, one of the components of the adenosine triphosphate (ATP) molecule, which is essential to energy metabolism.

“In a stressful situation or if the nervous system malfunctions, ATP consumption increases and more adenosine is released. The excess adenosine binds to the A2A receptors and triggers a cascading effect that sends this system into a spiral of deterioration,” Cunha said.

Because caffeine also binds to A2A receptors, it blocks the link with adenosine, cuts off the cascading effect and rebalances the system. “That’s why we feel more alert when we’re tired and consume caffeine,” Cunha explained. “It also increases tolerance to several signals that can cause hyperirritability in an individual.” In one of the experiments, the group administered to the same animal model a drug called istradefylline, which also inhibits A2A receptors and has been used to treat Parkinson’s disease. In this case, fewer symptoms of depression were observed in treated mice than in the control group.

“We knocked out the gene that expresses A2A receptors to show that this produced the same protective effect as caffeine. We also knocked out the gene only in key neurons to show that the effect we observed is present directly in the neuron and doesn’t depend on interaction with other systems,” Cunha said.

The group’s latest findings were published in May in the journal Proceedings of the National Academy of Sciences. For Cunha, they corroborate the results of epidemiological studies in humans.

“One of these studies followed more than 50,000 Hawaiian nurses for several years. Most of Hawaii’s population have the same lifestyle and diet. The conclusion was that individuals who consumed caffeine needed less psychiatric help,” Cunha said.

However, he stressed, new studies must be conducted to validate the A2A receptor as a target for treatment in humans.

“The main problem with transposing this information to human subjects is that humans are always far more complicated,” Cunha said. “Receptors are proteins that consist of chains of amino acids, and these chains may vary slightly from one individual to another. This genetic polymorphism is why people are more or less sensitive to caffeine.”

The Coimbra group is also endeavoring to find out whether inhibition of A2A receptors can prevent the cognitive changes associated with Alzheimer’s and similar diseases.

“In previous studies using animal models of Alzheimer’s we saw that the number of A2A receptors increases considerably when memory problems begin. This appears to be one of the causes of the disease and also represents an opportunity for treatment,” Cunha said.

Impaired brain development

Another research project, led by Christophe Bernard at the Systems Neuroscience Institute (INS), University of Aix-Marseille, France, evaluated the effects of caffeine consumption during gestation and lactation in mice.

Females were given caffeine in their drinking water in doses equivalent to a that of a human drinking two to three cups of coffee per day. After mating, caffeine administration continued at the same level throughout gestation and lactation.

The results were published in 2013 in the journal Science Translational Medicine.

“We found that caffeine causes a delay in the migration of a specific group of GABAergic neurons to the hippocampus,” Bernard told Agência FAPESP. “They reach the target but with a lag of several days. This impairs fetal brain development and causes an imbalance.” The hippocampus is the brain region associated with spatial memory and perception. GABAergic neurons secrete GABA (gamma-aminobutyric acid) as their primary neurotransmitter.

The effect was observed when analyzing the brain tissue of both mice and monkeys, the latter of which are more similar to humans.

In vitro analysis shows a 50% reduction in the speed of migration when caffeine binds to A2A receptors in neurons. “This suggests adenosine is necessary to the migration process. That’s one of the things we’re investigating at the moment,” Bernard said.

The French group also evaluated the effects of this delay on neural migration in offspring, and later in adult mice.

“Because of the imbalance caused by neural delay, infant mice become more susceptible to epileptic and febrile seizures. Their temperature threshold for thermal seizure is about 1.5 degrees Celsius lower,” Bernard said.

When the scientists evaluated the adult mice, they found that a different group of GABAergic neurons was missing, again causing an imbalance in brain functioning. “Behavioral tests showed that spatial memory was less efficient in the mice treated with caffeine than in control mice. The effect is subtle but definitely detectable. Of course, if caffeine had really bad effects on the brain, we would all know,” Bernard said.

Health professionals should try to investigate the role of caffeine consumption during pregnancy when children with convulsive crises or seizures are admitted to hospital and emergency rooms, Bernard argued. “This would enable us to try to find out whether caffeine consumption and an increased probability of epilepsy also correlate in humans,” he said.