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DOPAMINE

House M.D.

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One of the most important mediators of the central nervous system is a substance called dopamine. Dopamine has been known for a long time, somewhere since the middle of the XX century. It is a compound specifically associated primarily with the brain in compare to acetylcholine and nor-epinephrine, which are more active in the peripheral nervous system.
Dopamine is formed in our neurons as a result of a simple chain of chemical reactions, which originates from the amino acid - tyrosine. Then tyrosine turns into a molecule called L-DOPA, and already L-DOPA becomes dopamine. Moreover, L-DOPA in this chain is a precursor to dopamine, which further determines the use of the L-DOPA molecule as a medical drug. Dopamine is critical for the central nervous system, and dopamine neurons are found in three zones: this is the hypothalamus and two areas of the midbrain: the substantia nigra and the ventral tegmental area. In the hypothalamus, dopamine neurons have rather short axons, which mainly deal with intrahypothalamic problems and affect the release of certain hormones or the centers of some needs and are involved in regulation of autonomic nervous system - these are quite local functions, but important. For example, in the hypothalamus, dopamine can decrease food motivation, increase aggressiveness or increase libido, so these are local, but important functions.
The most famous are those dopamine neurons that are located just in the substantia nigra and the ventral tegmental region. The substantia nigra is so named because this area of the brain has a dark color: the neurons there contains a certain amount of melanin, a dark pigment. The axons of these cells go up to the cerebral hemispheres, and they mostly end up in the basal ganglia. This block of the dopamine system is associated with the regulation of motor activity - how much dopamine the substantia nigra secretes largely depends on how much a person is physically active, motorized, likes to move, moves willingly. People with an active black substance are happy to play sports, dance and generally move in space. People whose substantia nigra is not very active (and this mainly depends on genes) are motorily lazier and do not get so much pleasure from exercise, but they get pleasure from something else: from food or novelty. People around perceive them as lazy, which is incorrect because it's just a feature of the dopamine system.
Axons of the substantia nigra in the cerebral hemispheres pass into the basal ganglia. This is a very difficult area located in the depths of the cerebral hemispheres. When we talk about the cerebral hemispheres, we first of all remember the cortex, a zone that is located on the surface of the hemispheres and contains a huge number of nerve cells with a variety of functions. But in the depths of the cerebral hemispheres there are large clusters of neurons, which at one time were called basal ganglia. And there is a mass of anatomical structures:
  • Striatum;
  • Globus pallidus;
  • Claustrum;
  • Putamen.
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About 80% of the neurons of the basal ganglia in this group of structures are engaged in movement. It is the activity of these neurons that is affected by the substantia nigra. The remaining 20% of the basal ganglia are part of a different system related to needs, motivations, and emotions.
The area that deals with movement and is associated with the substantia nigra is often prone to a very characteristic disease called parkinsonism (Parkinson's disease). The problem is that the neurons of the substantia nigra turned out to be very "delicate", that is, among the many neurons of our brain, the cells of the substantia nigra are most susceptible to neural degeneration. Some neurons in this area accumulate pathologically abnormal proteins in their cytoplasm (they are called parkins) and begin to fail with age. As the substantia nigra feels worse and worse, the flow of dopamine to the basal ganglia becomes less and less, and for quite some time the basal ganglia successfully fight this, primarily by increasing the number of dopamine receptors.
When there is no longer enough resource, and parkinsonian symptoms begin to appear: trembling of the hands (tremor), muscle tension (rigidity) appears, it is difficult for a person to start movements (akinesia). This is a rather severe movement disorder we are trying to treat. The main drug that helps is L-DOPA, a precursor of dopamine. This substance can be given in the form of tablets to person with parkinsonism for a long time and stop this symptomatology, but unfortunately, the introduction of this substance does not stop neurodegeneration, so the dose has to be constantly increased for ten, fifteen, sometimes even twenty years.
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The second area is tegmental area. The axons of this zone go to the cerebral cortex and to that part of the basal ganglia that deals with just needs, motivations and emotions. Dopamine, produced by neurons of the tegmental area, in the cerebral cortex, largely determines the speed of information processing and the speed of our thinking. If there is a lot of dopamine in this system and the tegmental area is active enough, then we see that information processes go quickly, and a person has a fast brain. Such people can very successfully engage in mathematics, programming and in general professions related to abstract thinking. In addition, this same block gives us positive emotions associated with novelty. This is an essential component of our mental life because our brain is very curious and obtaining new information is biologically very important: we must know what is changing in the world around us, quickly detect and analyze these changes. For a person engaged in science or art, this is the most important component of mental life because to compose or discover something is simply wonderful. It turns out that dopamine is associated with positive emotions that correlate with novelty, creativity, humor. If you laugh, it's the release of dopamine too.
Unfortunately, this system may not work very well either. If it works poorly for some reason (mainly genetic), then a person lacks positive emotions associated with novelty, and this can be one of the components of depression. If this system works too hard, then thinking can become excessively fast, twitchy. A person cannot concentrate and think the same thought for a long time. Sensor systems begin to generate signals at a time when there are no real stimuli. All this results in symptoms, which are called schizophrenia. Unfortunately, schizophrenia is a very common disease: from 0.5 to 1% of the population suffer from this disease. In this case, drugs are needed that weaken the activity of the dopamine system from the group of neuroleptics, which are blockers of dopamine receptors.
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Dopamine has quite a lot of receptors, but allows you to distinguish five main types. If we look at different parts of the brain, we first of all find D-2 receptors that inhibit various nervous processes. And quite a lot of D-1 receptors - dopamine receptors of the first type, which activate various nervous processes. In some neural networks, D-1 and D-2 receptors are inserted as competing blocks, D-2 receptors limit D-1 activity. This is very well observed in the basal ganglia. If we start using dopamine receptor antagonists, the degree of severity of their effects depends on which receptors we fall for.
The history of neuroleptics begins with a substance called chlorpromazine. It is a crude neuroleptic that acts not only on all types of dopamine receptors, but also on norepinephrine receptors. But chlorpromazine in the history of psychiatry has become the most important drug, with the help of which for the first time it was possible to stop both severe schizophrenia and severe manic disorders at the pharmacological level. More selective drugs began to be created, mainly blocking the activity of D-2 receptors, in the 1960s. Modern neuroleptics are precisely blockers of D-2 receptors of varying degrees of effectiveness because softer drugs are more in demand. Fortunately, mild schizophrenia is more common than severe schizophrenia. Even from the point of view of the pharmacological market it is much more important to produce light neuroleptics because they have a much wider distribution.
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The main target of the action of neuroleptic drugs is the cerebral cortex and that part of the basal ganglia that is associated with emotions, needs, motivation. There are two structures in the basal ganglia: one is called the amygdala and the second structure is nucleus accumbens. These two structures are the most important targets for neuroleptics, and the nucleus accumbens is very actively studied as a key center associated with the generation of positive emotions. Most of the information flows associated with the fact that our body has successfully performed some activity: eaten or escaped danger, learned something new or successfully multiplied - go through the nucleus accumbens. And further signals from this structure, rising into the cerebral cortex, determine the processes of learning and memory formation. Therefore, this zone is very actively studied, and dopamine in this chain is the most important mediator.
It is possible to activate both the processes of thinking and the centers of positive emotions, including nucleus accumbens, if dopamine receptor agonists are used. Such drugs are known. And they belong to the group of psychomotor stimulants. A classic psychomotor stimulant is amphetamine - a substance discovered at the beginning of the XX century, which has passed a complex history. They tried to use it as a drug that causes weight loss, and as a psychomotor stimulant, sports doping and sometimes used in the clinic for severe depression. The same category includes very powerful narcotic drugs like cocaine, methamphetamine, mephedrone, MDPV and others which greatly increase the activity of the dopamine system and very quickly cause the formation of addiction and dependence, seriously changing the state of neural networks and especially the centers of positive emotions. Such as nucleus accumbens, which ultimately affects psycho-cognitive patterns.


The level of dopamine is directly related to these functions:
  • Logic;
  • Abstraction;
  • Symbol/language;
  • Mathematics;
  • Inspiration to the future;
  • Internal locus of control;
  • Technical and engineering thinking.
Hyperdopamine personalities (often autistic) have the highest intellectual abilities. High level of dopamine in the caudate nucleus is associated with a greater desire to actively use their cognitive abilities and make mental effort. People with higher levels of dopamine are more forward-looking, more likely to use abstractions and symbols, love logic, mathematics and technology.
DOPAMINE LEVEL.
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Let's imagine two people of the same weight and height. Both have 40,000 dopamine receptors (example) in their brains, but their sensitivity is different. In one person, the sensitivity of the receptors is reduced by 10 times, and the other is normal. Both people see the same pleasant sight, for example - a cute cat. This action causes the production 10,000 molecules of dopamine (example), i.e. the level of dopamine in both is the same. But what is the perception of this event? In this case, the first person has satisfaction by 25%, and the other - by 2.5%.
The first person will focus on how cute the cat is. And the second will think: the cat is cute, but he has toxoplasmosis and generally starves to death on the street. And with each such event, the first person will believe that his day was a success, and the second? The second will, of course, be unhappy with the day. Reduced dopamine levels reduce our ability to notice "rewards" – something positive and increases sensitivity to anxiety, to "threatening".
The first person will almost never suffer from dissatisfaction with himself throughout his life, but he will have few incentives for personal development. He will be satisfied if he is just full, dressed for the weather, etc. He will almost never want to change something for the better in himself or in life. But this person is not profitable for the consumer society: it is very difficult to force him to buy something and change something.

The second person is bound to be unhappy with something. He can always strive to fix something for the better, but it will not bring him pleasure. And it is likely that such a person will look for strong stimulants to produce 40,000 molecules of dopamine, and he has a high risk of addiction.
The second important point is associated not with pleasant moments, but with problems. If the first person screws up and his dopamine production drops (by 20,000 molecules, for example), then he will feel worse by 50%. And this will make him avoid an unpleasant situation in the future, i.e. learn from mistakes. But in the second person, the state of health will decrease by only 5%. That is, such a reduction is clearly not enough for him to fix conclusions.
Perhaps the lack of dopamine receptors reduces the ability of people to learn from their own mistakes and to draw the right conclusions from negative experiences, and not to repeat actions that led to bad consequences. In general, the results obtained suggest that the normal functioning of the dopamine systems of the brain is necessary for a person to be able to effectively learn from their mistakes. Disruption of dopamine neurons (for example, due to a lack of dopamine receptors, as in carriers of the A1 allele) can lead to ignoring negative experiences. There are several mutations in the genes of dopamine receptors. In the case of addictions, you can pass the analysis in order to choose the right tactics of therapy for such patients.
 
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keend478

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and there is only that type, or is there more
 

BHBlueberry

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I have tried L-Dopa and I can clearly say that it is simply ineffective. The only nice thing I can say about her? it? is that she? it? smells really awesome.

My observations are telling me that probably - supplemented (I took orally) L-Dopa is not passing the blood-brain barrier. I would recommend to use dopamine-precursor-precursor Tyrosine instead.

The opposite situation takes place when we talk about serotonin. 5-HTP was working very noticeable but the serotonin-precursor-precursor Tryptophan was simply ineffective.
 

Novator

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For me, L-Dopa turned out to be a real discovery. 5-HTP (combo with N-Acethyl-L-Tyrosine and DMAE) are separately familiar and has weak characteristics.
My recipe is to combine serotonin and dopamine drugs. But be careful!!!
The first time I did't know the dosages and woke up in the hospital isolator. I tried to crash the door use a couch. The police arrived on alarm. I calmly explained to the good guys, that they did not let me go to the toilet for a long time (there is no toilet in the isolator). And they need to remember, I am not a dog for medical staff. If not for a strong isolator, everything would break in my way to the old white friend.
But the experience is interesting. I repeated it in other dosages and removed from this combination one extra drug. It turned out great! Without harm. Time accelerated the same as last time, but without failures in memory. The clarity of the mind remained stable. All decisions and actions, in this state, were super -productive.
Next I write recipe, but... DONT USE IT WITH OTHER DRUGS (very danger):
Carbidopa (250mg) + Levodopa (25mg) + 5-HTP (50mg) + Idebenone (30mg).

First time also I added this combination: Amanita Muscaria (3 random hats) and Mucuna Pruriens (200mg) (have a nice trips NO 🤪)

But I can be mistaken in combinations. Because the black hole in memory after the first time left a very big impression.
 

Paracelsus

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I have tried L-Dopa and I can clearly say that it is simply ineffective. The only nice thing I can say about her? it? is that she? it? smells really awesome.

My observations are telling me that probably - supplemented (I took orally) L-Dopa is not passing the blood-brain barrier. I would recommend to use dopamine-precursor-precursor Tyrosine instead.

The opposite situation takes place when we talk about serotonin. 5-HTP was working very noticeable but the serotonin-precursor-precursor Tryptophan was simply ineffective.
In what dosages have you taken L-Dopa and for how long? How did Tyrosine show itself in your experience?
 

Paracelsus

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Next I write recipe, but... DONT USE IT WITH OTHER DRUGS (very danger):
Carbidopa (250mg) + Levodopa (25mg) + 5-HTP (50mg) + Idebenone (30mg).
For its intended purpose, Carbidopa and lLevodopa are usually taken in combination with at least 1:4. And the maximum daily dose of Carbidopa is 75-200 mg in several doses. Exceeding 200 mg of Carbidopa does not entail an increase in the therapeutic effect.

The average daily dose of Carbidopa required to suppress the peripheral conversion of Levodopa is 70-100 mg. The daily dose of Levodopa should not exceed 2000 mg - but this is a very large number and is needed specifically for the treatment of pathology.

Think about adjusting the scheme.
 
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