Trait#48: Dopamine Metabolism (COMT)
Monday, January 6, 2020. Author FitnessGenes
Monday, January 6, 2020. Author FitnessGenes
Dopamine is a substance that often comes up in the press, it's the pleasurable “feel-good” chemical that gets released by the brain in response to food, drugs, sex and rewarding social interactions.
Far from solely being involved in reward and addiction, however, dopamine (DA) is both an important hormone (a chemical message transported in the bloodstream) and neurotransmitter (nerve signalling molecule) that plays a variety of roles, including:
Along with noradrenaline and adrenaline, dopamine belongs to a class of related chemicals known as catecholamines.
Dopamine is a key neurotransmitter in the brain and central nervous system.
Neurotransmitters are chemicals that transmit a signal from one nerve (or neuron) to another, across a gap called a synapse.
When a dopaminergic nerve is stimulated, dopamine is released from special storage chambers called synaptic vesicles. Dopamine then travels across a synapse, binds to and activates a receiving or post-synaptic nerve. In this way a signal is passed from one neuron to another.
Dopamine transmits signals between neurons in large brain networks that control movement, reward, motivation and emotion.
Dopamine and control of movement
Whenever we make a complex movement, our brain makes a plan of movement and then sends out electrical signals which are ultimately transmitted down nerves (called motor neurons) to muscles, where they elicit muscle contraction.
Within the brain, there are various circuits or loops that fine-tune and co-ordinate our movement plans. One key component of these loops is our basal ganglia – a collection of interconnected structures deep within the cerebral hemispheres (see the area highlighted orange in the diagram below).
The basal ganglia contain networks of both inhibitory and excitatory neurons, allowing it execute the appropriate planned movements while dampening down unwanted movements.
For example, if you wanted to perform a controlled bicep curl, your basal ganglia activate plans associated with flexion and relaxation of bicep and tricep muscles. Additionally, your basal ganglia will help to inhibit undesirable movements e.g. outward adduction of your deltoids, allowing you to perform a bicep curl in one simple plane of movement.
So, where does dopamine fit in? Your basal ganglia and wider brain circuits involved in the control of movement are rich in dopaminergic neurons: nerves which use dopamine to communicate with one another.
More specifically, your basal ganglia contains an important chain of dopaminergic neurons called the nigrostriatal pathway. This pathway is particularly important in the control of movement. To highlight this fact, damage to the nigrostriatal pathway may cause movement disorders such as Parkinson’s disease (which is characterized by difficulty initiating movement, rigidity of muscles, slowness of movement and tremor).
Dopamine, reward and motivation
In the popular press, it’s often been said that dopamine is the ‘pleasure molecule,’ which directly causes feelings of pleasure. In reality, dopamine’s role in pleasure and reward is a bit more complicated.
Studies suggest that dopamine plays a role in reward learning – the process of associating a pleasurable sensation with a particular stimulus (e.g. food, drugs, video games, exercise).
For example, you may experience pleasure the first time you eat chocolate. Your brain will subsequently associate the sight, smell, taste and texture of chocolate with a pleasurable experience. This may then motivate further behaviour to obtain and consume chocolate (we call this reinforcement in psychological terms).
The process of linking stimuli to pleasurable experience is mediated by a network of structures in the brain known as our reward system. Our reward system is particularly rich in dopaminergic neurons, which become activated in response to rewarding stimuli such as food, sex, drugs etc.
Recent research in neuroscience suggests that we have different brain networks responsible for ‘liking’ and ‘wanting’ rewarding stimuli.
Returning to the chocolate example, we may have a pleasurable experience whenever we eat chocolate. This is the ‘liking’ aspect of reward. By contrast, if we were to see someone else eating chocolate, this may trigger a desire to eat chocolate ourselves. This is the ‘wanting’ aspect of reward.
Our brains attribute a ‘want’ or, more formally, incentive salience, to the chocolate. This ‘want’ then gets activated by various cues (for example seeing someone else eating chocolate). As a result of ‘wanting,’ we go on to perform behaviors that lead to consumption of the rewarding stimulus. When we see someone else eating chocolate, we may be motivated to go to the vending machine and buy a chocolate bar to eat ourselves.
Dopamine plays a prominent role in this ‘wanting’ or incentive salience of rewarding stimuli. Specifically, a specialized network of dopaminergic neurons known as your mesolimbic dopamine pathway is thought to underlie incentive salience.
A key structure in the mesolimbic dopamine pathway is the ventral tegmental area (VTA) (see diagram of dopamine pathways below). Interestingly, this brain area is implicated in addiction, obesity and our response to palatable, high-calorie food.
Dopamine and control of blood pressure
In addition to acting as neurotransmitter in our brain and central nervous system, dopamine acts a hormone in wider tissues in the body. One of the major hormonal roles of dopamine is to regulate blood pressure and blood volume.
Dopamine produced by the adrenal glands circulates in the bloodstream, where it can act on a variety of tissues. When dopamine binds to receptors on blood vessel walls, it causes them to dilate (a process called vasodilatation).
As we learned in your Vascular Smooth Muscle Contraction trait, the dilation of blood vessels leads to an increase in blood flow to target organs as well as a drop in blood pressure.
- Dopamine and kidney function
Dopamine is also produced by cells lining the tubules of your kidneys.
When dopamine binds to receptors in your kidneys, it inhibits the reabsorption of sodium ions back into the bloodstream. Another way of looking at it is to say that dopamine increases the excretion of sodium ions into the urine.
As mentioned in your Renin-Angiotensin-Aldosterone System trait, water tends to follow the movement of sodium ions. As more water and sodium ions are excreted into the urine, there will be a fall in blood volume and drop in blood pressure.
Finally, dopamine also inhibits the release of adrenaline and noradrenaline. Both adrenaline and noradrenaline may cause either vasodilatation or vasoconstriction and therefore influence blood pressure.
Within the brain and central nervous system, dopamine is mainly made by nerve cells (neurons).
Outside of the brain, dopamine is made by the adrenal glands. These are a pair of glands that sit just above the kidneys and are also responsible for producing various other hormones, including adrenaline, aldosterone and cortisol. Dopamine made by the adrenal glands is released into the bloodstream, where it can act on various tissues, including blood vessels.
Other specialized groups of cells also produce dopamine. For example, cells in the tubules of kidneys secrete dopamine, which helps with the control of blood pressure and volume.
Dopamine is made using the same biochemical pathways that produce adrenaline (and noradrenaline).
In this respect, dopamine, like adrenaline, is derived from the amino acid tyrosine.
To recap from your adrenaline trait, amino acids are the building blocks of protein. Tyrosine is a non-essential amino acid, meaning it can be made endogenously by the body. In this case, tyrosine can be made by converting another amino acid, phenylalanine. Phenylalanine is an essential amino acid, meaning it must be consumed in the diet.
Given their role in the synthesis of dopamine, an adequate dietary intake of phenylalanine and/or tyrosine is needed to produce healthy levels of dopamine.
Tyrosine --> L-DOPA
In the first step of the pathway, tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase (TH). This enzyme uses BH4 (tetrahydrobiopterin) as a cofactor. We’ve met BH4 before in your BH4 Synthesis and Recycling Trait.
L-DOPA --> Dopamine
In the second stage, L-DOPA is converted into dopamine by the enzyme DOPA decarboxylase (also known as aromatic L-amino acid decarboxylase). This enzyme uses the active form of Vitamin B6, pyridoxal phosphate, as a cofactor.
Dopamine works by binding to specialized dopamine receptors on the surfaces of nerves and other cells.
There are 5 main types of dopamine receptor: D1, D2, D3, D4 and D5. These types of receptor differ in their structure, function and distribution. For example, your basal ganglia (which helps to control movement), is particularly rich in D2 receptors. By contrast, your kidneys tend to express D5 type receptors.
When dopamine binds to a dopamine receptor, it triggers a cascade of chemical reactions. These chemical cascades ultimately modify other key molecules (e.g. enzymes, ion channels, other neurotransmitter receptors), which are responsible for the effects of dopamine. For example, when dopamine binds to D1 receptors on neurons, it opens specialized calcium ion channels, which then stimulates nerve activity.
As with adrenaline, dopamine is broken down by enzymes.
Three key enzymes are responsible for the breakdown (or metabolism) of dopamine:
Together these enzymes metabolize dopamine into a molecule called HVA (homovanillic acid).
The activity of these enzymes influences both your levels of dopamine circulating in the bloodstream and levels of dopamine within synapses between nerves.
Why is the degradation of dopamine important?
In the brain and central nervous system, the COMT, MAO and ALDH enzymes are responsible for terminating nerve signals.
As mentioned previously, dopamine is a neurotransmitter – a chemical used to transmit signals from one nerve to another across a synapse. After dopamine is released by a (pre-synaptic) nerve, it travels across a synapse and then binds to dopamine receptors on another (post-synaptic) nerve, where it stimulates nerve activity. Shortly afterwards, dopamine is released back into the synapse (or synaptic cleft).
If dopamine were allowed to linger in the synapse, it would constantly stimulate the post-synaptic nerve, giving rise to inappropriate nerve signals. The COMT, MAO and ALDH enzymes ensure that dopamine is quickly broken down and the nerve signal is shortly terminated.
If we have reduced activity of these enzymes, however, levels of dopamine within the synapse will remain high. This may cause increased activity in dopaminergic nerves and wider brain networks.
Conversely, if the activity of these enzymes is excessively high, levels of dopamine in the synapse will be low, giving rise to low activity in dopaminergic nerves and brain networks.
Therefore, the activity of COMT, MAO and ALDH enzymes influences overall nerve activity in brain circuits that use dopamine.
As these brain circuits control our reward, motivation and control of movement, changes in enzyme activity can affect our more complex behaviors.
As mentioned above, the activity of enzymes that break down dopamine will significantly influence our dopamine levels in nerve synapses and therefore the activity in dopaminergic brain circuits.
Research shows that variations in the genes encoding these enzymes can affect their activity, which in turn, affects our (synaptic) dopamine levels.
In this respect, variations in your COMT, MAO and ALDH genes can all affect your dopamine level. Your latest Dopamine Metabolism trait focuses on variants of your COMT gene.
COMT gene variants
At FitnessGenes we analyze SNPs (Single Nucleotide Polymorphisms). SNPs (pronounced “snips”) are single letter changes in your DNA code.
There is one SNP (rs4680) that occurs in your COMT gene, which gives rises to two gene variants.
One variant, called the ‘G’ allele, is associated with higher activity of the COMT enzyme. This causes greater breakdown of dopamine and therefore gives rise to lower levels of dopamine in the blood and in dopaminergic brain networks.
By contrast, another variant, called the ‘A’ allele, changes the structure of the COMT enzyme causing a 25-40% reduction in enzyme activity. Consequently, the ‘A’ allele causes reduced breakdown of dopamine and higher levels of dopamine in brain networks.
Worrier vs Warrior
As dopamine plays key roles in brain circuits that underlie behaviour, variants of our COMT gene can influence how we behave and respond to everyday life situations.
In fact, our COMT gene is sometimes known as the worrier/ warrior gene.
People with the ‘A’ allele are more likely to have high levels of dopamine. During times of stress, when dopamine production is increased, people with the ‘A’ allele are more prone to anxiety, as dopamine levels become excessively high. Such individuals are termed ‘worriers.’
By contrast, people with the ‘G’ allele have lower levels of dopamine, but are better able to deal with psychological stress. These individuals are termed 'warriors.'
Given its wide-ranging roles, low levels of dopamine within various brain circuits can have widespread effects on exercise and nutrition.
If you’ve ever trained too hard or too frequently, you may have experienced fatigue. Your muscles are tired and it’s difficult to exert and sustain a force. Previously, much of this fatigue was explained by changes in the structure and function muscle, as well as the peripheral nerves supplying them.
More recent research suggests that fatigue may also be caused by impairment in the way our brain sends motor signals down to our muscles. This type of fatigue is known as central fatigue, as it arises from changes to our brain and central nervous system.
On this note, low levels of dopamine may increase the risk of central fatigue.
Reduced motivation to perform exercise
Lower synaptic dopamine levels have been associated with a reduced intrinsic drive to perform exercise.
In one study, people were given a diet that was depleted of phenylalanine and tyrosine. Both these amino acids are ordinarily used by the body to make dopamine. When fed the diet of a long period, levels of dopamine in brain circuits fall. Healthy people fed this diet were less motivated to exercise.
Increased risk of eating unhealthy foods
People with lower dopamine levels in their reward system may be at greater risk of impulsively consuming high-calorie foods.
Increased susceptibility to stress
Like adrenaline and noradrenaline, dopamine is also a catecholamine that is released in response to acute stress. People with ordinarily high synaptic levels of dopamine may therefore be more liable to anxiety and stress, as dopamine levels become excessively high.
Dopamine plays a role in promoting wakefulness. It is possible that high levels of dopamine may interfere with the ability to fall asleep.
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