For this post, I want to discuss an idea that is rather nuanced and complex: how to chronically upregulate dopamine (DA) levels.

You can find hundreds of articles on “how to boost dopamine”, but this is only half the story. In reality, it’s not as simple as merely boosting a neurotransmitter and expecting a positive result.

In order to explain this distinction, I will need to provide a brief overview of some key brain mechanisms, namely homeostasis and synaptic transmission. If you want to skip ahead you can feel free to do so, but this information is worth knowing.

A Brief Lesson in Neurochemistry

Synaptic Transmission

The image above is a simplified illustration of synapse, which is connection between two nerve cells (neurons).

The brain contains about 100 billion neurons, and neurons are connected to one another in a complex web of synapses. There are over 100 trillion synapses in the brain, and each one is used to send and receive chemical signals from neurons.

Neurotransmitters are created and stored in pre-synaptic neurons as seen at the top of the illustration. Once released, they are absorbed by the post-synaptic neurons as seen at the bottom.

Both pre-synaptic and post-synaptic neurons contain receptors that regulate how much a neurotransmitter is released and how much it is absorbed. When DA is flooded into a synapse, it will “vacuum up” any excessive DA back up into pre-synaptic receptors.

Drugs like cocaine work preventing this “vacuuming” effect (typically by blocking the action of a transporter called DAT). This process is commonly referred to as reuptake inhibition. Antidepressants like Zoloft and Prozac share this mechanism, but act as serotonin reuptake inhibitors instead.

Homeostasis

The brain is constantly trying to maintain homeostasis: a stable, steady state of equilibrium. If you abuse a drug like cocaine, your brain will be constantly flooded with unnaturally high amounts of DA. Your brain will recognize this, and will respond by downregulating the amount of post-synaptic receptors, decreasing your sensitivity to DA.

In reality, these neurological processes are much more complex than this, but this will give you a general idea of how homeostasis works. Many people who are familiar with these basic concepts will understand the limitations of trying to raise DA levels.

These feedback mechanisms partially explain why drugs like cocaine are so addictive. Once the effects of the drug wear off, repeated doses will be required to maintain high levels of DA. Over time, baseline DA levels will decrease due to this downregulating effect.

These self-correcting steady-state mechanisms of the brain are not limited to drugs of abuse; the brain is constantly making adjustments to maintain a consistent state, from even the most trivial of activities.

Methods of Upregulation

Fortunately, there do appear some effective ways of increasing average DA levels over the long-term. This list will include both supplements and physical tasks; I will attempt to explain the mechanisms behind each in relationship to this goal.

Uridine

Uridine is a naturally-occuring nutrient and nootropic that is critical for brain function. It is ubiqitous in nature as it used to form RNA in the brain and is produced in the bodies of all living creatures.

Uridine works by repairing dopaminergic neurons and preventing overstimulation in the striatum.

By preventing overstimulation of striatal DA receptors, uridine may help promote more stable and consistent levels of circulating DA in the brain.

Accordingly, uridine has been shown to enhance DA release through potassium channels. In rats, striatal DA levels were measured after 6 weeks of supplementation. DA release was shown to be significantly higher in treated rats; the treatment group had basal DA levels of 341+/-21%, while the control group had basal DA levels of 283+/-9%. This measurement was seen after both 1 and 6 weeks of supplementation.

Taken together, it would appear that uridine may upregulate DA by both preventing excessive DA levels and by repairing/restoring neuronal DA functionality.

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CDP-Choline

CDP-Choline, also called citicoline, is a naturally-occuring compound and nootropic that is typically supplemented to improve cognitive performance.

In one study, CDP-choline was provided to aged rats over the course of seven months. After seven months, levels of striatal DA were measured. In the one treated group, a dose of 100mg/kg was used, and an 11% increase of DA receptor densities was found. In the another treatment group, a dose of 500mg/kg was used, and this time a 18% increase was found.

Interestingly, a third group received no citicoline at all, and they showed a 28% decrease in receptor density. This is because DA receptor densities decrease with age, at a rate of about 3% per decade.

The exact mechanism by which cdp-choline upregulates DA is unclear. However, CDP-choline does provide neuroprotection for dopaminergic neurons , and this protection play a key role.

It should be noted that the differences between the treatment groups and the nontreatment group was quite significant. Additionally, given that rat lifespans are quite short, 7 months is quite a long time, which suggests these changes may be permanent.

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Forskolin

Forskolin is an herbal extract that is touted for many alleged health benefits. It has many interesting properties that warrant further research, but one of the lesser-known properties of the plant is its effect on DA receptors.

Forskolin has been noted to upregulate DA receptor densities quite significantly. In the first study I will be referencing, supplementation was shown to modify two unique DA receptors: D2L, and D2S.

D2L : a “long form” post-synatic receptor, which allows DA to get absorbed and utilized

: a “long form” post-synatic receptor, which allows DA to get absorbed and utilized D2S: a “short form” pre-synaptic receptor, which regulates DA synthesis, storage, and release

In regards to receptor densities, forskolin increased D2L receptor densities by 43%, and increased of D2S receptor densities by 107.5%.

In short, what this study suggests is that the brain:

Becomes sensitized to DA by increasing its availability to be absorbed Becomes more effective at regulating DA release, which may maintain stable DA levels over the long-term.

In the next study, rats were directly injected with forskolin into their cerebrospinal fluid for 5 days. Afterwards, it showed the same results as the previous study; increases in both the post and pre synaptic densities. Interestingly, D1 receptor densities were decreased.

In this third study relating to forskolin supplementation, similar results were found. In rats, D2L receptor densities were increased by 43-96%, which indicated DA supersensitivity.

The results of this are a bit more ambiguous, especially in regards to the ratio of receptor changes. However, as the 3rd study indicated, it would appear that forskolin does in fact lead to DA sensitization in the brain through modulatory effects on DA receptor densities.

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Inositol

Inositol, also referred to as Vitamin B8, is a molecule that is structurally similar to glucose. It is critical for cellular signalling in the brain and facilitates communication between neurons.

Inositol is considered a pseudovitamin, as inositol is metaboized in the kidneys from glucose. However, it may be a key nutrient in regulating mental health, and deficiencies have even been implicated in schizophrenia.

There is some emerging evidence that suggests inositol may be able to elevate DA levels over a long period. One notable study was conducted recently to determine the effects of inositol on mental health by analyzing its effects on various neurotransmitters.

In this study, guinea pigs were given oral inositol (1.2 g/kg) for 12 weeks (about 15-20g a day for humans). The result were promising: chronic inositol induced a significant increase in striatal D2 receptor density. There was no data on whether this effect is maintained after treatment nor the degree to which the densities were changed depending on dosages used.

Inositol is known to be a key signalling agent for neurotransmission, which may be enhanced by regular supplementation. As such, upregulation may occur in part due to the increased cellular communication.

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Exercise

Lately, the mental health benefits of exercise are gaining a lot of traction. There is now an increasingly large amount of evidence that exercise can increases DA receptor availability in the striatum.

In one study, exercise was shown to reduce the neurological damage that occurs from methamphetamine abuse. Adult men and women with methamphetamine dependence were given supervised exercise therapy while recovering. After exercising for three days a week for 8 weeks, the treatment group showed a significant increase in striatal D2/D3 function.

One rat study showed similar results. Rats were subjected to eight weeks of a food-reinforced running-wheel exercise. Levels of DA were noted to be upregulated after the eight week period, although a compensatory downregulation of the receptor densities was also noted.

The upregulatory effects of exercise on DA levels does not not appear come from modulating receptors. Rather, it was found that DA binding affinity was increased.

Additionally, this study suggested that exercise training upregulated DA by increasing levels of serum calcium. This is because the enzyme responsible for DA synthesis (tyrosine hydroxylase) is partially mediated by calcium influx in the brain.

It’s unclear which form of exercise is most effective. A mix of weight training, HIIT, and cardio is generally a safe bet.





Sunshine Exposure

Here’s another behavioral change you can implement to increase DA sensitivity. In this study, the goal was to identify the correlation between sunshine exposure and DA levels. This was accomplished by comparing 68 volunteers who had either high levels of sunlight exposure or low levels sunlight exposure.

The study found that striatal D2/D3 receptor availability was significantly greater in the group with high exposure than the low exposure group. This was even after controlling for age, sex, and smoking status. Furthermore, this does not appear to be related at all to Vitamin D levels. This means that sunlight is not only essential for synthesizing vitamin D in the body, but also for dopaminergic regulation.





Meditation

While scientific evidence on meditation is still in its infancy, there is emerging evidence of many incredible benefits to brain health and function. There are two studies which show that meditation modestly increase DA levels, although effect did not appear permanent unless it was practiced regularly.

One very interesting study measured spontaneous eyeblink rates, which is strongly correlated with striatal DA activity. Here, the authors stated that meditation has been shown to affect cognitive functions such as mind wandering, cognitive flexibility, and attention. These cognitive functions, in turn, were shown to be correlated with eyeblink rates as well.

The goal of this study was to determine the effects of long-term meditation on eyeblink activity; the results of which can be used to infer the effects on striatal DA levels.

Both long-term meditators and new meditators were examined over 8 weeks of a mindfulness-based stress reduction course. The long-term meditators were found to have blinked less often and had a different pattern from the the new meditators.

The study concluded that “long term meditation practice induces stable changes in baseline striatal DA functioning.”

The authors mentioned that individual differences in DA function may have acted as a self-selection factor in meditation practice. In other words, people with specific DA levels are more likely to practice meditation. While this is a possibility, I find it very unlikely that this accounts for every individual case. More studies are urgently needed.





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