Higher levels of glutathione in the nucleus accumbens correlated with better and more steady performance in motivation-based tasks


In life, motivation can be the difference between success and failure, goal-setting and aimlessness, well-being and unhappiness. And yet, becoming and staying motivated is often the hardest step, a problem which has prompted much research.

A very small part of that research has looked into the question of metabolism. “Do differences in metabolites in the brain affect our capacity for motivation?” asks Professor Carmen Sandi at EPFL’s School of Life Sciences.

“If that is the case, could nutritional interventions that can affect metabolite levels be an effective vehicle to improve motivated performance?”

Sandi’s group, with their colleagues at the Nestlé Institute of Health Sciences, have now published a study that shines the first light into answering that question. The researchers focused on an area deep into the brain called the “nucleus accumbens”, which is known to play a major role regulating functions like reward, reinforcement, aversion, and not least, motivation.

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, as a result of its metabolism.

What is oxidative stress? As cells “eat” various molecules for fuel, they produce a number of toxic waste products in the form of highly reactive molecules collectively known as “oxidative species”. Of course, cells have a number of mechanisms in place to clear oxidative species out, restoring the cell’s chemical balance. But that battle is ongoing, sometimes that balance is disturbed and that disturbance that’s what we call “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.

To answer the question, the scientists looked at the brain’s most important antioxidant, a protein called glutathione (GSH), and its relationship to motivation.

“We assessed relationships between metabolites in the nucleus accumbens – a key brain region – and motivated performance,” says Sandi. “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

First, they used a technique called “proton magnetic resonance spectroscopy,” which can 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.

What they found was that higher levels of GSH in the nucleus accumbens correlated with better and steady performance in the motivation tasks.

GSH levels and motivation

But correlation does not imply causation, so the team moved on to live experiments with rats that were given micro-injections of a GSH blocker, downregulating the synthesis and levels of the antioxidant. The rats now showed less motivation, as seen in a poorer performance in effort-based, reward-incentivized tests.

On the contrary, when the researchers gave rats a nutritional intervention with the GSH precursor N-acetylcysteine – 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,” as the authors write.

Can nutrition or supplements help motivation?

“Our study provides novel insights on how brain metabolism relates to behavior and puts forward nutritional interventions targeting key oxidative process as ideal interventions to facilitate effortful endurance,” conclude the authors. The study’s findings “suggest that improvement of accumbal antioxidant function may be a feasible approach to boost motivation.”

“N-acetylcysteine, the nutritional supplement that we gave in our study can also be synthesized in the body from its precursor cysteine,” says Sandi. “Cysteine is contained in ‘high-protein foods’, such as meat, chicken, fish or seafood. Other sources with lower content are eggs, whole-grain foods such as breads and cereals, and some vegetables such as broccoli, onions, and legumes.”

“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.”

N-acetyl-L-cysteine (NAC), the acetylated precursor of L-cysteine, is used in medicine as a mucolytic agent to treat drug toxicity or overdose, given orally, intravenously, or by inhalation [1]. Though these uses are well established, there has been much recent interest in the use of NAC in treating neuropsychiatric conditions, including schizophrenia, mood and anxiety disorders, and substance-use disorders (SUDs). In the following, we review the growing body of research evidence for therapeutic benefits of NAC in psychiatric disorders and the potential mechanisms by which it may exert these beneficial effects.

We conducted literature searches in PubMed/MEDLINE and Google Scholar using the key terms “NAC”, “N-acetyl-L-cysteine”, “psychiatric disorders”, “mental illness”, and terms specific to each disorder. Manual searches were done of the bibliographies of included studies. Studies included are those that were published before December 2021. We discuss the potential therapeutic mechanisms of NAC in psychiatric disorders as well as the published literature pertaining to each individual psychiatric disorder. Within each psychiatric disorder, the underlying neurobiological deviations will be explained, followed by preclinical literature, and lastly (clinical) human literature, when available. The disorders are grouped and ordered as per their appearance in DSM-5, with the exception of Williams Syndrome, which does not appear in DSM-5 but was placed under neurodevelopmental disorders in this paper; onychophagia, which is not listed in DSM-5 but is generally considered an obsessive-compulsive-related disorder (OCRD); and Chronic Pain, which likewise is not in DSM-5 and was placed at the end of the paper.

Potential Therapeutic Mechanisms of N-Acetyl-L-Cysteine (NAC)
NAC has multiple relevant actions including antioxidant effects, reduction of cytokine activity, modulation of dopamine release, reversal of mitochondrial dysfunction, reductions in apoptosis and ferroptosis, anti-inflammatory activity, increased neurogenesis, and increased glutamate release [1,2,3,4,5,6,7,8,9,10]. Perhaps the most important of these for the treatment of psychiatric disorders is its antioxidant activity, which it achieves through multiple mechanisms. NAC functions as an antioxidant through stimulating the synthesis of glutathione, enhancing glutathione-S-transferase activity, scavenging free radicals, and stimulating group II metabotropic glutamate receptors to decrease glutamate transmission [2]. Glutathione is the primary endogenous antioxidant in the brain. Its production rate is limited by L-cysteine availability, so increasing the supply of L-cysteine via NAC supplementation leads to an increase in brain glutathione [3].

Antioxidants reduce oxidative stress, which is implicated in the pathogenesis of many psychiatric disorders [11]. Oxidative stress represents a state in which there is an imbalance between reactive oxygen species, such as hydrogen peroxide, superoxide, and peroxynitrite, and tissue redox defenses. It can be the result of having increased reactive oxygen species, decreased antioxidant defenses, or unrepaired oxidative damage [12]. Reactive oxygen species cause cellular lipid peroxidation, inactivation of important enzymes, malfunction of the respiratory chain, and DNA modification [11, 12]. Antioxidant enzymes, such as superoxide dismutase, glutathione reductase and peroxidase, metabolize reactive oxygen species into less toxic molecules, protecting the brain from harms caused by oxidative stress [12]. Severe prolonged oxidative stress can lead to glutathione depletion via the increase in glutathione disulfide formation and accumulation, leading to export and extracellular hydrolysis, protein S-glutathionylation, and formation of glutathione adducts [13]. Oxidative stress is linked to mitochondrial dysfunction, which NAC has been shown to prevent [4, 5].

NAC is most frequently used in paracetamol toxicity, where mitochondrial protein adducts are formed causing oxidative stress that eventually leads to liver failure [14]. NAC prevents this through its action as a glutathione precursor, thus supporting mitochondrial metabolism [14]. Mitochondrial dysfunction is a common element linked to bipolar disorder, depression, schizophrenia, and autism spectrum disorder (ASD) [4, 7, 15]. In bipolar disorder, mitochondrial overactivity is associated with mania and under functioning is associated with the depressed and euthymic phase of the disorder [15]. NAC has also been shown to increase mitochondrial complex I- and IV-specific activities in synaptic mitochondrial preparations in aged mice [16].

The anti-inflammatory activity of NAC is protective against chronic inflammation, which is implicated in the pathogenesis of many psychiatric disorders [17]. Chronic inflammation is characterized by elevated pro-inflammatory cytokines and acute phase proteins. Patients acutely unwell with depression or schizophrenia are more likely to have raised inflammatory markers, and patients who have chronic inflammatory conditions, such as lupus or rheumatoid arthritis, are at a higher risk of developing depression or schizophrenia [18]. Moreover, inflammation and psychiatric disorders are genetically linked, for example, the risk of developing schizophrenia is associated with polymorphisms in the major histocompatibility complex on chromosome 6 [18]. Anti-inflammatory treatment may improve the therapeutic efficacy of antidepressants, especially in patients with high baseline levels of inflammation [6]. Increased oxidative stress and increased inflammation are intimately linked, and NAC has both antioxidant and anti-inflammatory properties [6]. NAC has immuno-modulation activity, having been demonstrated to reduce the levels of inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), nuclear factor kappa B (NF-κB), IL-6, and IL-10 in rodents [1, 5].

NAC also modulates the glutamatergic system, dysfunction of which is linked to multiple psychiatric disorders [5, 19]. By forming cystine outside the cells, NAC drives the astrocytic cystine–glutamate antiporter, which increases intracellular cysteine for glutathione synthesis and simultaneously extrudes glutamate into the extracellular space [7]. Rising concentrations of extracellular glutamate stimulates presynaptic metabotropic glutamate receptors, which decreases the synaptic release of glutamate [7]. Glutathione may also have a role in regulating glutamate levels in the brain as it has been shown to potentiate brain N-methyl-d-aspartate (NMDA) receptor response to glutamate in rats [7].

NAC has also been demonstrated to alter dopamine release in animal models [7]. At sufficiently high doses, it has been demonstrated to reduce striatal dopamine in rats given amphetamines; however, that same study found that at lower doses NAC increased striatal dopamine release [20]. NAC has also been shown to reduce methamphetamine-induced reduction of dopamine transporters in the striatum of rhesus monkeys [16]. NAC may reduce dopamine through facilitating increased glutathione production, which has a significant role in reducing oxidative stress. Amphetamine use is associated with excessive release of dopamine and suppressed action of dopamine metabolites [20]. Glutathione increases glutamate agonist-evoked striatal dopamine release likely via glutathione’s activity at NMDA and non-NMDA glutamate receptors [21].

reference link :https://link.springer.com/article/10.1007/s40263-022-00907-3

Original Research: Open access.
Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort,” by Ioannis Zalachoras et al. eLife


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