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NAC May Help Boost Motivation by Addressing Oxidative Stress

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Getting and staying motivated is hard for many people. In fact, it is such a frequent problem that scientists have invested much time and research into the topic.

Now, a new study in the journal eLife reveals that motivation is influenced by oxidative stress in the brain. And, according to the same study, nutritional therapies such as NAC supplements may help increase motivation by targeting this oxidative stress.

Metabolism and Oxidative Stress in the Brain

The idea behind the study was that the brain itself — like all tissues in our body — is subjected to constant oxidative stress because of its metabolism. The researchers focused on an area deep into the brain called the “nucleus accumbens,” which is known to play a key role in regulating functions like reward, reinforcement, aversion, and motivation.

As cells “eat” various molecules for fuel, they produce numerous toxic waste products in the form of highly reactive molecules collectively known as “oxidative species.” Of course, cells have several mechanisms in place to clear oxidative species out, restoring the cell’s chemical balance. But sometimes that balance is disturbed, resulting in oxidative stress.

The Glutathione Connection

The brain then is often subjected to excessive oxidative stress from its neurometabolic processes – and the question for the researchers was whether antioxidant levels in the nucleus accumbens can affect motivation. Scientists looked at the brain’s most important antioxidant — glutathione (GSH) and its relationship to motivation.

“We assessed relationships between metabolites in the nucleus accumbens — a key brain region — and motivated performance,” says lead researcher Carmen Sandi, professor at EPFL’s School of Life Sciences. “We then turned to animals to understand the mechanism and probe causality between the found metabolite and performance, proving as well that nutritional interventions modify behavior through this pathway.”

Tracking GSH in the Nucleus Accumbens

The researchers, from EPFL and Nestlé Institute of Health Sciences, used a technique called “proton magnetic resonance spectroscopy,” which helps assess and quantify the biochemistry in a specific region of the brain in a non-invasive way. The researchers applied the technique to the nucleus accumbens of both humans and rats to measure the levels of GSH.

They then compared those levels to how well or poorly their human and animal subjects performed in standardized, effort-related tasks that measure motivation. They found that higher levels of GSH in the nucleus accumbens correlated with better and steady performance in motivation-related tasks.

GSH Levels and Motivation

Of course, correlation does not imply causation, so the team moved on to live experiments with rats given micro-injections of a GSH blocker, downregulating the synthesis and levels of the antioxidant. The rats showed less motivation, performing worse in effort-based, reward-incentivized tests.

On the contrary, when the researchers gave rats a nutritional intervention with the GSH precursor N-acetylcysteine (NAC) — which increased GSH levels in the nucleus accumbens — the animals performed better. The effect was “potentially mediated by a cell-type specific shift in glutamatergic inputs to accumbal medium spiny neurons,” say the authors.

“Of course, there are other ways beyond N-acetylcysteine to increase GSH levels in the body, but how they relate to levels in the brain – and particularly in the nucleus accumbens – is largely unknown. Our study represents a proof of principle that dietary N-acetylcysteine can increase brain GSH levels and facilitate effortful behavior.”


“We establish GSH levels in the NuAc [nucleus accumbens] both as a predictive marker of differences in reward-based effortful performance and as a potential target for nutritional or other type of interventions. We also provide strong evidence for a promising potential of chronic NAC supplementation to boost accumbal GSH levels and to regulate motivation to exert reward-incentivized effort. However, it is important to note that our sample sizes are relatively small, and thus the absence of significant effects should be interpreted with caution. As our studies were performed in male humans and rodents, it is important to note as a limitation to our findings. We are currently expanding our studies to female populations, where we hope to find similar relationships between GSH and motivated behavior.”



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