Dopamine diseases

Viktor Lebedev, "Biomolecule"The human brain is a tangle of many nerve fibers, along which various signals go.

Despite its electrical nature, the signal can be transmitted from one cell to another only with the help of special substances – neurotransmitters. It is they who transmit information at the point of contact of two neurons – the synapse. One of the neurotransmitters is dopamine; this substance is associated with the most important biological processes in the brain and serious diseases.

Three waysDopamine is a fairly simple molecule.

A benzene ring with two hydroxyl groups, a short chain of two carbon atoms with an amino group at the end – this is the structure of one of the most influential substances in our body. In addition to its simple structure, dopamine also has a short synthesis pathway (Fig. 1).

Figure 1. Dopamine synthesis (from the website biochemistry.terra-medica.ru ).

In the human body, a hydroxyl group is attached to the essential amino acid phenylalanine – this is how L-tyrosine is obtained. With continued hydroxylation, it turns into dihydroxyphenylalanine. When carbon and oxygen atoms are taken away from the latter from the side chain, i.e. decarboxylation occurs, a dopamine molecule is formed. Many have heard that sometimes "dopamine" is pronounced instead of "dopamine". This is due to the different spelling of the short name of the precursor substance dihydroxyphenylalanine in English and Russian. In English, it is spelled DOPA (dihydroxyphenylalanine). In Russian, the abbreviation looks different: DOPA (dihydroxyphenylalanine). Derivatives of these molecules will be called respectively by abbreviations – dopamine in English and dopamine in Russian.

If a substance plays an important role in the nervous system, then there must also be receptors for it - the point of application of the substance. Now there are 5 types of dopamine receptors. They are called predictably boring: DRD1, DRD2, DRD3, DRD4 and DRD5. The DRD1 and DRD5 receptors belong to one group, and the other types belong to another. When dopamine interacts with receptors of the first group, a cascade of reactions is triggered, leading to an increase in the intracellular concentration of cyclic adenosine monophosphate (cAMP), and when reacting with other types of receptors, the amount of cAMP decreases. That is, the interaction of dopamine with different groups of receptors leads either to activation or to inhibition of cellular activity. And this in turn has an impact on human behavior [1].

Dopamine highways are laid in the brain in three main directions (Fig. 2). The first road (mesolimbic path) leads from the ventral region of the tire (ventral tegmental area, VTA) to the limbic system – the part of the brain in which our emotions and desires are formed. The second route is laid between the VTA and the frontal cortex (mesocortical pathway): cognitive processes are carried out here, as well as processes related to motivation and emotions. It is easy to see that the mesolimbic and mesocortical pathways perform similar functions. They are responsible for the formation of desires, motivation and emotional reactions in all people. There is a third way – nigrostriar, linking the black substance (substantia nigra) with the striatum (striatum). The nigrostriatal pathway has a special function: in the nervous system, it triggers motor activity, reducing tension in the muscles.

Figure 2. Dopamine pathways. The nigrostriar pathway controls movements,
mesolimbic and mesocortical are involved in higher mental functions (Post files, 2013).

Molecular GingerbreadYou can often read that dopamine is a neurotransmitter of pleasure, but this is not entirely true.

Dopamine helps the brain choose the right behavioral strategies and creates motivation for specific actions. Mesolimbic and mesocortical dopamine fibers are involved in these processes.

In a visual presentation, the participation of dopamine in the learning process will look like this. A person paints a fence and gets paid for it. There is an action (painting a fence) and a reward (money) that the brain links together. The first monetary reward for painting the fence leads to the release of dopamine. In the future, the allocation of dopamine in time will shift not to receiving a salary for work, but to the work itself. This is how motivation is formed, based on benefits, on the positive emotions received. If after the action for which the motivation was formed, the expected reward did not arrive, then the amount of dopamine in the corresponding structures of the brain decreases, reducing the value of this action. If you paint a fence, and you don't get paid for it or pay too little, then in the end you will leave the brush and paint (Fig. 3).

Figure 3. Dopamine release when receiving and not receiving a reward. The upper part – the action is performed, dopamine is produced in response to the reward – the "action – reward" connection is consolidated. The middle part – the surge of dopamine activity is shifted to the action itself, which shows the formed connection between the action and the expected reward. Receiving a reward no longer causes a rise in dopamine levels. The lower part – if the expected reward is not received after the action performed, the dopamine level decreases, reducing the value of this action in the future (from the article jn.physiology.org/content/80/1/1 ).These simple mechanisms control our whole life – from praise in kindergarten to voting against the candidate who does not suit us.

It is noteworthy that when receiving a reward and its absence, neurons with different types of dopamine receptors are involved (Fig. 4). In the case of receiving a reward, the activity of neurons with a type 1 dopamine receptor changes, and in its absence, with a type 2 dopamine receptor [2].

Figure 4. Involvement of different dopamine pathways in learning. When receiving a reward greater than expected, neurons with dopamine receptors of type I are excited. When the reward is less significant than before, the activity of cells with type II dopamine receptors decreases (from [2]).In addition, there are such schemes of dopamine pathways that respond with arousal to negative stimuli [3].

With this in mind, it becomes clear that dopamine is not associated with pleasure, but with motivation and the formation of purposeful behavior. Dopamine fibers penetrate into various parts of the brain – the prefrontal cortex, responsible for planning and learning, the hippocampus (the center of our memory) – and form stable functional connections between neurons for the implementation of behavioral programs.

Disorders in various dopamine pathways lead to various diseases.

Observant DoctorAt the beginning of the XIX century, a doctor practicing in north-east London published a short work "Essay on trembling paralysis".

In the essay, he described a disease whose symptoms were trembling of the hands at rest and increased muscle tone. He also described in detail the nature of the disease, the speed of its course: "The signs of this disease are so small and almost imperceptible and its development is so extremely slow that it rarely happens that the patient can form some kind of memory about the exact date of its onset" [4]. The author of these words was James Parkinson.

Parkinson's disease is a disease in which brain structures that are part of the nigrostriatal dopamine pathway are affected. In Parkinson's disease, the alpha-synuclein protein accumulates in the neurons of the black matter, which leads to disruption of the functioning of cells and their death. Under the microscope, protein accumulations are visible in the form of granules – the so-called Levi bodies (Fig. 5).

Figure 5. Neuron with a Levi's body – a pathological cluster
alpha-synuclein protein in the cytoplasm (from the website medschool.ucsf.edu ).

To understand what happens with the disease, first you need to deal with the norm. In a healthy person, signals from the black matter through the processes of dopamine neurons enter the striatum. Impulses from the motor centers of the cerebral cortex go there, but along the glutamate pathways. Signals come through the dopamine pathways that affect muscle tone and make movements smooth. Glutamate signals are sharp contractions of skeletal muscles. In Parkinson's disease, dopamine neurons gradually die off, and the intensity of impulses gradually decreases. This happens unnoticed for a long time, the remaining cells use power reserves. Sooner or later, the signal power drops critically. As a rule, this happens when 3/4 of the neurons of the substantia nigra die. There are signs of the disease – an increasing increase in muscle tone and trembling of the hands. In the early stages of the disease, the patient retains the ability to purposeful actions, but the further it progresses, the more difficult it is for a person to perform simple everyday actions, for example, holding a spoon.

Parkinson's disease is manifested not only by specific motor disorders. In addition to the black matter, other parts of the brain are involved in the pathological process; this leads to the appearance of the so-called non-motor symptoms of Parkinson's disease. Sleep disorders, low mood, anxiety, weight gain or loss, vision problems, slow thinking and even dementia – the list of symptoms is impressive, and often the patient is prevented from living even by non-motor disorders, namely non-motor manifestations of the disease.

One of the main drugs for Parkinson's disease is levodopa – the L-isomer of dioxyphenylalanine (L-DOPA), which penetrates the brain better than dopamine itself. However, a relatively small part of levodopa penetrates into the brain, and the remaining amount begins to be converted by peripheral tissue enzymes into dopamine by decarboxylation. Excess dopamine can lead to a drop in blood pressure, fainting and other unpleasant side effects. To avoid this, in addition to levodopa, peripheral L-DOPA decarboxylase inhibitors are prescribed. There are antiparkinsonian drugs where levodopa is already combined with an enzyme inhibitor, and they increase the effectiveness of treatment (Fig. 6).

Figure 6. Pathophysiology of disorders in Parkinson's disease. A – before treatment: the glutamate signal (green arrow) does not change in Parkinson's disease, the intensity of dopamine exposure (black arrow) decreases, there is a functional advantage of the glutamate system. B – after the use of drugs, the strength of the dopamine signal increases, the system comes to equilibrium. Motor disorders decrease. The author's drawing.

The dopamine hypothesisAnother disease that is closely related to dopamine is schizophrenia.

During the discussion of the origin, diagnosis and treatment of this disease, the spears of more than one generation of doctors, scientists, psychologists, journalists and others involved were broken. In order not to go into the wilds of this dispute, it is worth giving a brief description of the modern approach to schizophrenia. Firstly, schizophrenia exists, and it is a disease. Secondly, she has clear diagnostic criteria that any psychiatrist is familiar with. Despite the variety of clinical manifestations, schizophrenia is well recognized by specialists. In addition to diagnostics, treatment has been developed and proven to work successfully. This is the third. But we will return to the treatment later.

The various symptoms of schizophrenia are usually divided into three groups. The first includes positive symptoms – something that is added to a person's mental activity: auditory and visual hallucinations, ideas of persecution, exposure to radiation. The second group is negative symptoms. This term denotes the patient's loss of what was inherent in him earlier. Negative symptoms include: a decrease in daily activity, loss of interests and a decrease in emotional manifestations, both internal (the strength of emotions, their diversity) and external (the expression of emotions on the face). As a rule, a group of negative symptoms is described in the specialized literature by the term "emotional-volitional decrease". Outside of the exacerbation of schizophrenia, they determine the condition and quality of life of a person with schizophrenia. The third group includes cognitive symptoms – specific problems with information processing.

In the early 50s, the first version of the dopamine hypothesis was put forward. Doctors used experimental antipsychotic drugs and for the first time received persistent improvements in drug treatment. In the course of research, it turned out that these drugs reduced the effect of dopamine on nerve cells. Psychiatrists began to associate the occurrence of schizophrenia with an excess of dopamine in the nervous system. Over the next 40 years, new data accumulated, and by the end of the 20th century, the dopamine hypothesis was revised. Positive symptoms (delusions, hallucinations) began to be associated with an excess of dopamine in the mesolimbic pathway, and negative symptoms – with its deficiency in the mesocortical pathway. Moreover, the excess of dopamine, which leads to what is called psychosis – "voices" and paranoia – is probably caused by increased dopamine release in the subcortical parts of the brain, and not by increased sensitivity of neurons to the substance [5].

Familiar side effectsCurrently, special antipsychotics are used to treat schizophrenia.

They block dopamine receptors, reducing the excessive effect of dopamine on the neuron. Antipsychotics are divided into typical (haloperidol, aminazine) and atypical (risperidone, quetiapine); typical antipsychotics were synthesized earlier than atypical ones. The fundamental difference between the two groups of drugs is in the spectrum of symptoms they affect. The target of the "old" drugs were mainly hallucinations and delusions, i.e. positive symptoms, and the target of the new generation were also negative symptoms of schizophrenia. The difference in clinical effects may be explained by the fact that atypical antipsychotics significantly affect other neuronal receptors (for example, serotonin).

The problem of using drugs of different generations is related to the fact that typical antipsychotics cause motor side effects more often than atypical ones [6]. Side effects often occur in the form of muscle stiffness and trembling of the hands, which is very similar to Parkinson's disease. The complex of these symptoms is called medicinal parkinsonism. The antipsychotic blocks all receptors in the brain indiscriminately and sooner or later reaches the nigrostriatal system, reducing the effect of dopamine signals on the motor structures of the nervous system. The patient may complain of muscle stiffness, trembling of the hands, and these are some of the most unpleasant side effects that often lead to refusal of treatment. At the very beginning of the history of the use of antipsychotics, doctors believed that until a person developed motor disorders, the dose of the drug could not be considered adequate. Fortunately, reasonable treatment regimens for mental disorders have now been developed and applied, and the drugs from the new group of antipsychotics have less pronounced motor side effects.

Literaturebiomolecule: "Thin threads of fate";

2. Bromberg-Martin E.S., Matsumoto M., Hikosaka O. (2010). Dopamine in motivational control: rewarding, aversive, and alerting. Neuron. 68 (5), 815–834;
3. Matsumoto M. and Hikosaka O. (2009). Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature. 459, 837–841;
4. Hurwitz B. (2014). Urban observation and sentiment in James Parkinson’s Essay on the Shaking Palsy (1817). Lit Med. Spring, 74–104;
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6. Leucht S., Corves C., Arbter D., Engel R.R., Li C., Davis J.M. (2009). Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. The Lancet. 373 (9657), 31–41.

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