Vitamin C, Depression, and Chronic Stress

Mental or emotional states such as depression or anxiety have been receiving a lot of scientific attention lately, especially the interplay between vitamin C and depression.

A group of researchers used a vitamin C deficiency animal model, gulo -/- mice, and studied the subsequent behaviors that emerged. Gulo -/- mice are used to study vitamin C deficiency because they do not have the gene that produces the protein (gulonolactone oxidase) which is involved in the last step of ascorbic acid synthesis. So, gulo -/- mice need to acquire vitamin C through dietary intake and if they have a diet restricted in vitamin C, they become vitamin C deficient.

The three conditions that were included in the researchers’ experiment were:

A control group, C57Bl/6J wild-type mice

The control gulo -/- mice, fed a regular diet

The experimental gulo -/- mice, on a diet deficient of ascorbic acid[4]

The researchers included two control groups in order to be able to compare their behavioral differences which might exist even though both came from similar genetic backgrounds. Such considerations are important because animal strains can show subtle differences in behaviors which may, in turn, affect results during statistical analysis. For example, in this experiment, the wild-type control mice traveled less distance in the Elevated Zero Maze than the control gulo -/- group did. Although the control groups remained similar in other parameters of the Elevated Zero Maze, such as the time spent in closed zones, the effect of controls is still an important consideration to take into account when designing animal studies.

The researchers interpreted that the vitamin C deficient mice had depressive symptoms given their results in the Tube Dominance Test, an apparatus that is designed to measure winning conflict situations and social hierarchy. The vitamin C deficient mice had the shortest trial times, indicating that they were submissive and backed out of the situation quickly. Furthermore, even when the vitamin C deficient mice were given ascorbic acid (later on, in an attempt to “resuscitate” them), their trial length did not increase and the researchers concluded that this was a form of depression, specifically behavioral despair.

Behavioral differences were supplemented by biological alterations in the animals’ brain. The vitamin C deficient mice had more oxidative damage in the proteins and lipids found in the cortex. Also, the cortex and striatum had decreased levels of serotonin and dopamine metabolites which, with a more longitudinal experimental design, might have triggered more behavioral problems to emerge.

In a different experiment, also aiming to study the interaction between vitamin C and depression, researchers induced depression mice via the chronic unpredictable stress model. The chronic unpredictable stress model (CUS) was constructed to mimic the environmental factors that contribute to the formation of depression and has a strong face, construct and predictive validity.

The researchers wanted to explore the relationship between vitamin C, depression, and chronic stress in mice by running behavioral and biochemical tests after inducing CUS and treating it.[5] They paid particular attention to reactive oxygen species because chronic stress has been shown to increase the amount of reactive oxygen species available in the brain. Furthermore, depression has been linked to related biomarkers of oxidative stress, as demonstrated by studies that have examined depressed patients’ lipid peroxidation levels and blood levels of circulating antioxidant enzymes.

The untreated CUS mice exhibited increased immobility during the Tail Suspension Test, an effect that was reversed in the group of mice that had CUS-induced depression but were treated with ascorbic acid. In fact, the ascorbic acid treated group performed at the level of the CUS-induced group that was treated with fluoxetine, a commonly administered antidepressant drug. Reducing immobility in the Tail Suspension Test is a significant finding because increased immobility is a behavioral marker for depression in animal studies. Therefore, the researchers were able to conclude that vitamin C is able to reduce some of the problems associated with depression.

During the biochemical analysis, CUS-induced mice that did not receive treatment showed increased lipid peroxidation levels, as established by measured produced levels of thiobarbituric acid reactive species (TBARS) in both the hippocampus and the cerebral cortex. However, ascorbic acid treatment in the CUS-induced depressed mice was associated with a significant decrease in the hippocampus’ TBARS levels, a sign of decreased lipid peroxidation. The fluoxetine group, on the other hand, showed decreases of TBARS levels in the cerebral cortex.

The behavioral and biochemical profiles acquired from this experiment contribute to the growing body of knowledge that vitamin C and depression are related. However, further research needs to occur, in order to unravel the mechanisms and extent to which vitamin C can affect both mood and behavior.