We know that neurotransmitters are very important in several functions of both the central nervous system, including the brain, and the peripheral nervous system.
And, therefore, we have several posts on neurotransmitters, such as: norepinephrine , adrenaline and serotonin .
What have you heard about dopamine? Did you know that it is involved in a number of functions and mechanisms in our body?
You may be in doubt as to whether or not you know this substance, but you, for example, have certainly heard of some diseases in which dopamine is a protagonist such as Parkinson’s Disease, among others that we will see below.
Today we are going to talk about this important substance, and to know its functions and actions in our organism.
What is dopamine?
Dopamine is a neurotransmitter, of the catecholamine family, which acts in some brain areas and plays an important role in them.
Dopamine is produced by dopaminergic neurons, and this production takes place from the amino acid tyrosine, as seen in the image below. Tyrosine is converted to L-DOPA, which is decarboxylated to form dopamine.
Figure 1: Dopamine Synthesis
At the nerve endings where dopamine is released there are dopamine transporters, which capture it to be metabolized.
The main enzymes that carry out this metabolization are: monoamino oxidase ( MAO ) and catechol-O-methyltransferase ( COMT ).
This metabolization generates some metabolites, hydroxyphenylacetic acid (ADHFA) and homovanilic acid ( AHV) .
How important is that? This AHV in the brain serves as a dopamine renewal index, that is, it carries the information that dopamine has been metabolized so it is necessary to produce more.
Dopamine, to perform its effects, binds to its receptors. There are 5 receivers: D1 , D2, D3, D4, and D5.
They were grouped into families D1 and D2, according to their mechanism of action, with D1 and D5 belonging to family D1. The D2, D3 and D4 receivers belong to the D2 family. And what is the difference between them?
The D1 family acts by promoting the activation of the Gs protein, stimulating adenylcyclase and leading to an increase in cAMP.
The D2 family acts by inhibiting adenylcyclase and thus there is no increase in cAMP or they act in other ways that do not involve adenylcyclase, such as promoting the opening of K + channels, or inhibiting Ca + channels, or even potentiating the release of arachidonic acid.
These different receptors are found in different pathways and thus perform different functions.
The main receptors, the most common and most found, are D1 and D2.
The D1 receptor is the most common dopamine receptor in the nervous system, it is present in the cerebral cortex, in the limbic system and in the striatum.
Therefore, when activated, it acts in some different functions such as: control of mood, emotion and behavior, in addition to modulating the secretion of prolactin.
The D2 receptor, like the previous one, is present in the cerebral cortex, in the limbic system, in the striatum, and besides these in common, it is also present in the ventral portion of the hypothalamus and in the anterior pituitary.
Thus, when activated, it helps to control mood, emotion and behavior, and modulates prolactin secretion (it is present in two areas that perform this control – striatum and ventral portion of the hypothalamus and the anterior pituitary).
The D3 receptor is present in a small amount in the limbic system, in the striatum and in the ventral part of the hypothalamus and anterior pituitary.
Thus, it assists in functions such as emotion and behavior and prolactin secretion.
The D4 receptor is present in low concentrations in the cortex, in the limbic system and in the striatum, and thus interferes with mood, emotion, behavior, and prolactin secretion.
Finally, the D5 receptor is present in low concentrations in the limbic system and in the striatum.
Thus, it acts in functions such as emotion and behavior, and secretion of prolactin.
And now that we have seen some information about dopamine, such as its synthesis, metabolism, and receptors to which it binds, we come to a very interesting part, because, understanding these dopaminergic pathways, we will also understand the functions of dopamine.
Figure 2: Dopaminergic pathways
There are four ways:
- Via Nigroestriada
- Mesolimbic route
- Mesocortical pathway
- Tuberofacial pathway
Figure 3: Black pathway
This pathway is the main one because it makes up about 75% of the brain’s dopamine. The name of this path is due to the location of dopaminergic neurons.
The cell bodies are found in the substantia nigra, located in the midbrain, and the axons are directed to the striatum, where they end.
Figure 4: Black substance
This pathway is closely related to the control of motor activity . This control of our movements is carried out in such a way that, when we want to make a movement, we do not need to think, that is, we are able to move “automatically”.
The nigro-striated pathway is associated with the extrapyramidal system, the direct and indirect path of movement.
The extrapyramidal system includes some structures such as thalamus, cerebellum, basal ganglia (lentiform nucleus – formed by the putamen and pale globe -, caudate nucleus, substantia nigra and subtalamic nucleus). This set of structures works by performing motor control .
Talking about the basal ganglia, the putamen and the caudate nucleus functionally correspond to a structure, which represents the pathway of entry of the basal ganglia circuit, and receives afferent fibers from the substantia nigra pars compact that release dopamine, and this acts at the D2 receptor inhibiting striatal neurons that target the lateral pale, and can also act at D1 receptors promoting the excitation of striatal neurons that target the medial pale + pars reticulated substance .
The pars reticulated black substance and the pale globe, functionally form another structure, which represents the pathway out of the circuit, and protrudes into the thalamus, from where fibers leave for the motor and pre-motor cortex. These two functional complexes are related in two ways: the direct route and the indirect route.
The direct pathway is an inhibitory pathway, mediated by GABA and substance P. It occurs through the interaction between the neostriate and the pale medial + pars reticulated substantia nigra , with inhibition of the latter. With this there is no inhibition of the thalamus, and thus, the activation of the cerebral cortex occurs.
The indirect pathway is an excitatory and inhibitory pathway. The relationship of the neostriate and the lateral pale, and the relationship of the lateral pale and the subthalamic nucleus are inhibitory, being mediated by GABA.
The relationship between the subthalamic nucleus and the medial pale complex + pars reticulated substantia nigra is mediated by GLUTAMATE, thus being excitatory.
The end result of the indirect route is the thalamus inhibition and thus the cerebral cortex is not activated.
Figure 5: Direct and indirect routes
Figure 6: Mesolimbic pathway
The mesolimbic pathway , also known as the reward pathway , is composed of dopaminergic neurons, the cell bodies being located in the ventral tegmental area in the midbrain, and the nerve fibers go to the nucleus accumbens and the tonsillar nucleus , which are part of of the limbic system.
This path is related to our reward system , acting on our behavioral responses and control of affective behavior.
How does this work in the reward system? This happens because, the dopamine released in this way and acting in the nucleus accumbens , promotes the regulation of incentive and reward.
It is also important in the perception of pleasure.
Figure 7: Mesocortical pathway
The mesocortical pathway , as well as the mesolimbic pathway, is made up of dopaminergic neurons, whose cell bodies are located in the ventral tegmental area , the difference being that their fibers project into the frontal cortex .
This path is related to emotional and behavioral aspects, such as the control of affective behavior.
It has an important relationship with the anterior route, the mesolimbic route.
Figure 8: Tuberoinfundibular pathway
The tuberoinfundibular pathway , also known as the puberty-pituitary system, has dopaminergic neurons that start from the hypothalamus to the median eminence and to the pituitary.
Thus, it interferes and modulates pituitary secretions . Dopamine acts in this way as an inhibitory neurotransmitter, inhibiting the production of one of the hormones produced by the anterior pituitary gland, which is prolactin .
Now that we have talked about these pathways and some dopamine functions in these pathways, let’s talk about dopamine associated with some disorders and situations.
Dopamine and Parkinson’s Disease
Parkinson’s disease is a neurodegenerative disorder that affects the nigrostriated pathway , specifically its dopaminergic neurons. It is a disease that mainly affects the elderly.
For some reason, these individuals exaggerate dopaminergic neurons in this region and thus develop Parkinson’s disease.
Signs and symptoms
The disease develops with some important signs and symptoms such as bradykinesia (slow movements) or akinesia (absence of movements), joint stiffness , tremor at rest , and postural instability (imbalance).
Bradykinesia or akinesia is one of the classic symptoms of the disease. There is difficulty in initiating the movement and maintaining it.
Joint and limb stiffness is also noted. The muscles are contracted causing this stiffness.
The tremor noted in resting disease is more intense at rest , in addition to being asymmetrical , that is, it is more intense on one side of the body, and it is important to know that it will not always be present.
And postural instability and imbalance, as the patient has difficulty maintaining his posture, and thus, often starts to present a posture leaning backwards or forwards.
Figure 9: Individual with Parkinson’s – note the postural instability and the inclined position.
A very common confusion that occurs is between the disease and Parkinson’s syndrome . But what’s the difference? Parkinson’s disease refers to this disease that we are talking about, generated by the reduction of dopamine in the nigrostrayed pathway.
Parkinson’s SYNDROME, on the other hand, corresponds to a group of diseases that have the same symptoms as Parkinson’s disease. That is, Parkinson’s disease is contained in Parkinson’s syndrome, and makes up about 70% of the causes of the syndrome.
And why does it happen? What is the influence of dopamine?
With the destruction of dopaminergic neurons in the nigrostrayed pathway , and now you need to remember what we talked about how this pathway works. As we talked about earlier, the functioning of the nigro-striated pathway passes through some pathways and systems, which perform the control of cortical activation.
Dopamine reduction compromises the substantia nigra pars compact which would normally activate the neostriate to activate the direct and indirect pathways, and this impairment prevents this activation, and the result is that the reticulate nigra pars becomes predominant, promoting an inhibition of the thalamus and consequent cortical inhibition, that is, it inhibits the activation of movements.
Figure 10: Pathophysiology of Parkinson’s disease – The left side of the image shows the normal pathway, where there is the excitatory stimulus in blue and the inhibitory stimulus in red. Note on the right side that the stimuli are reduced, and thus there is no inhibition of the pars reticulated substantia nigra, which predominates over the thalamus, promoting its inhibition. With the inhibition of the thalamus, the cortical activation necessary to perform movements is reduced .
Some drugs, such as conventional antipsychotics, block the D2 receptor and thus prevent the action of dopamine. As a result, the patient may have Parkinson’s syndrome, as he has dopamine but the receptors are blocked, and so his action is not performed.
Thus, the patient develops the same symptoms seen in Parkinson’s disease – bradykinesia or akinesia, tremor at rest, joint and limb stiffness and postural instability.
Dopamine and Sleep
It is known that dopamine is one of the amines that make up the upward activating monoaminergic system , which plays an important role in the sleep-wake cycle , especially in wakefulness.
Studies show that in addition to this role in wakefulness, dopamine has an effect on sleep regulation. The dopaminergic system of substantia nigra pars compacta is involved in sleep regulation .
Some data that corroborate this information is that patients with Parkinson’s disease have sleep disorders, and experiments show that lesions of dopaminergic neurons are associated with sleep disorders.
Thus, dopamine is involved in both sleep and wakefulness.
Dopamine and Schizophrenia
If you’ve seen the Joker movie, you’ll understand why the photo below is associated with a text about schizophrenia. That’s right, the Joker has a psychotic disorder, he has schizophrenia and deals with it throughout the film.
Figure 11: “The Joker” movie
The Schizophrenia is a psychotic disorder, a complex mental disorder by interfering directly in the individual ‘s life. This is due to the fact that the disease leads to a loss of connection with the real, that is, he lives immersed in unreal thoughts and hallucinations.
The disease is marked by disturbances of dopamine levels in two areas: mesocortical and mesolimbic.
In the mesocortical pathway there is a reduction in dopamine , and as a result there are some symptoms known as negative symptoms which are:
- Affective dullness: the individual has difficulty expressing his emotions and feelings
- Social withdrawal
- Alogia: individual poor in expressions
- Anhedonia: the individual has loss of pleasure, reduced activity of the reward system
- Loss of initiative
- Loss of attention
On the other hand, in the mesolimbic pathway there is an increase in dopamine , and this hyperactivity of the pathway also leads to some symptoms, known as positive symptoms , which are very noticeable in patients with schizophrenia, which are:
- Control delirium
- Hallucinations, which can be auditory, visual or even tactile
- Disorganized behavior
Dopamine and Depression
The reward system allows us to have a reaction according to a given stimulus, so if something very good happens, this system promotes motivation and pleasure for the good reward.
What happens is that the individual generates a memory about such a reward, and this subsequently motivates him to a certain reaction to “earn his reward”.
Dopamine participates in this reward system, acting especially in the nucleus accumbens , which makes up the mesolimbic pathway.
Thus, the reduction of dopamine in the mesolimbic pathway is related to a dysfunction of the reward system, thus leading to depression.
There is a reduction in positive affection, and the individual presents depressed mood and loss of happiness from pleasure, enthusiasm, reduced self-confidence. The individual loses enthusiasm, becomes apathetic.
There are some treatments for depression with anhedonia, which work by increasing dopamine, such as the use of bupropion.
Dopamine and Dependence
As with depression, reduced dopamine can interfere with the brain’s reward system. It has also been seen that a deregulation of the mesolimbic pathway, especially in the nucleus accumbens , has an important relationship with the development and maintenance of addiction to some addiction, be it behavioral or chemical, such as drugs.
This happens because there is a reduction in the activation of the reward system, when the individual discovers some activity, some action that promotes activation of that system, he begins to repeat this action to obtain his reward, the pleasure, even if it is momentary (just that that makes him repeat this action constantly and involuntarily, making it an addiction).
Addiction is very common with drugs, such as cocaine, heroin. The reason is simple: these drugs increase the dopaminergic effect.
Heroin increases the release of dopamine by dopaminergic neurons and cocaine increases the availability of dopamine to its receptors.
With the increased dopaminergic effect on the brain’s reward system, the individual is able to achieve his reward, his pleasure.
Dopamine and Appetite
Dopamine also interferes with appetite, as seen in research that points to this interference due to the involvement of the reward system.
Under normal conditions, dopamine participates in the control of hunger.
In a change in the system and in the dopaminergic pathways, the individual may eat in larger quantities, involuntarily, in order to activate the reward system.
Dopamine, Prolactin and Lactation
Dopamine, produced in the tuberoinfundibular pathway, is the neurotransmitter that keeps the production of prolactin by the anterior pituitary inhibited throughout the woman’s life, except in breastfeeding, when prolactin performs its important function of producing milk.
Throughout this period of life when a woman is not breastfeeding, prolactin must be inhibited.
If there is a dopamine dysregulation, a reduction, this production is no longer inhibited, and with this there is an increase in the concentration of prolactin, causing hyperprolactinemia.
Hyperprolactinemia thus causes abnormal milk production (abnormal lactation).
Prolactin in turn inhibits the production of gonadotropins , and this can lead to changes in libido and other sexual dysfunctions, and dysregulation of the menstrual cycle in women, since the reduction of gonadotropins leads to a reduction in the production of sex hormones involved in the menstrual cycle, estrogen and progesterone.
Performance in the cardiovascular system
Dopamine also acts in the peripheral system, an example of which is its performance in the cardiovascular system.
Some vascular areas have dopaminergic receptors, especially the D1 receptor , as in the renal, mesenteric, coronary vessels, branches of the middle cerebral artery and splenic.
When this receptor is activated, there is an increase in cAMP, and with that, the vasodilation of these vessels.
This effect is of great importance in the kidneys, for example, as this vasodilation can be beneficial to maintain renal blood flow in certain situations.
Dopamine is also able to activate β (Beta) receptors . By activating β 1 receptors , it promotes effects on the heart, such as the positive inotropic effect (increasing the force of cardiac contraction) and positive chronotropic effect (increased heart rate).
It can also activate β 1 receptors , promoting vasodilation.
And dopamine can also activate α (alpha) receptors. This activation leads to effects on α 1 such as vasoconstriction.
So, we saw the effects of dopamine on the cardiovascular system. It has a greater affinity for dopaminergic receptors, followed by Beta receptors and finally alpha receptors.
By knowing its effects, dopamine is used in emergency situations. Thus, the dose used varies according to the desired effect.
When the desired effect is dopaminergic effects , low doses of dopamine (<5 mcg / kg / min) are used.
If the desired effects are the beta effects , such as increasing the force of cardiac contraction, intermediate doses of dopamine (5 – 10 mcg / Kg / min – beta dose) are used.
This effect may be necessary in situations such as severe bradycardia or atrioventricular block.
And if the effects are the effects generated by the activation of alpha receptors , such as vasoconstriction, high doses of dopamine (> 10 mcg / kg / min – alpha dose) should be used.
In shock situations, vasopressor amines are generally used to maintain peripheral vascular resistance, and dopamine is one of those amines that can be used.
Did you imagine that dopamine could be involved in so many systems? That so many effects could be achieved by a single substance?
I hope that today you have known a little about this substance so important for the correct functioning of our organism.