Dopamine

Dopamine (DA) is a peripheral vasodilator used to treat low blood pressure, low heart rate, and cardiac arrest, particularly in acute neonatal settings, by continuous intravenous drip.[ 1 ] Low infusion rates (0.5 to 2 mcg/kg per minute) act on the splanchnic vasculature, causing vasodilation, including the kidneys, resulting in increased urine output. Intermediate infusion rates (2 to 10 mcg/kg/min) stimulate myocardial contractility and increase electrical conduction in the heart, resulting in increased cardiac output. Higher doses cause vasoconstriction and increased blood pressure via alpha-1, beta-1, and beta-2 adrenergic receptors, potentially leading to peripheral circulatory collapse.[ 2 ]

Indications Dopamine

Indications for the use of Dopamine include maintenance of blood pressure in chronic heart failure, trauma, renal failure, and even open-heart surgery and shock from myocardial infarction or sepsis. Low-dose DA administration may also be useful for the treatment of hypotension, low cardiac output, and organ failure (often indicated by low urine output). DA acquired significant clinical importance in the central nervous system (CNS) after Horniewicz's experiments showed its reduction in the caudate nucleus of patients with Parkinson's disease. In addition, intravenous administration of its amino acid precursor, L-DOPA (L-dihydroxyphenylalanine), attenuates parkinsonian symptoms.[ 3 ] Because the blood-brain barrier prohibits DA from entering the CNS from the systemic circulation, DA is ineffective in central neurological disorders such as Parkinson's disease. However, L-DOPA successfully crosses the blood-brain barrier and can be administered systemically, including oral tablets. Although therapeutic dopamine replacement is effective in alleviating motor symptoms, it may result in motor side effects and addiction-related behavioral problems (e.g., impulse control disorders) [ 4 ], [ 5 ], [ 6 ]

Release form

Dopamine is available in ampoules as a concentrate for infusion solution.

Pharmacodynamics

Dopamine biosynthesis follows the same enzymatic sequence as norepinephrine (NE). In fact, DA is a precursor for NE synthesis (see Figure). [ 7 ], [ 8 ] The first step in DA synthesis is rate-limiting and involves the conversion of L-tyrosine to L-DOPA by the enzyme tyrosine hydroxylase (TH). [ 9 ], [ 10 ] This conversion requires oxygen, an iron cofactor, and tetrahydrobiopterin (BH4 or THB) and results in the addition of a hydroxyl group to the aromatic ring to form L-DOPA. This molecule is subsequently converted to DA by aromatic L-amino acid decarboxylase with the removal of the carboxyl group. Once synthesized, DA is transported into synaptic vesicles via vesicular monoamine transporter 2 (VMAT2) to synaptic terminals. [ 11 ], [ 12 ]

If a person regularly consumes L-tyrosine in large quantities, it easily crosses the blood-brain barrier, just like L-DOPA. [ 13 ] But its usefulness is spatially limited because DA cannot cross the blood-brain barrier. However, if L-tyrosine levels are low, L-phenylalanine can be converted to L-tyrosine by phenylalanine hydroxylase.

Once DA is released into the synaptic space, it interacts with various receptors on the pre- and postsynaptic terminals, causing excitation or inhibition of target neurons. There are two entire families of DA receptors, consisting of five different isoforms, each of which influences different intracellular signaling pathways.[ 14 ] Both families of dopamine receptors, D1 and D2, are by definition G protein-coupled receptors, but the D1 receptor class results in neuronal depolarization, whereas D2 receptors suppress neuronal excitation.[ 15 ]

Once in the synaptic cleft, DA is transported back into the presynaptic neuron via DA transporters (DATs) for repackaging or may remain in the extracellular space for uptake by glial cells or metabolism by the cell membrane. DA can be metabolized extraneuronally by catechol-O-methyltransferase (COMT) to 3-methoxytyramine (3-MT), while monoamine oxidase-B (MAO-B) rapidly metabolizes 3-MT to homovanillic acid (HVA).[ 16 ] Additionally, it can undergo metabolism within the cytoplasm, where the dual action of MAO-A and aldehyde dehydrogenase (ALDH) converts DA to the phenolic acid 3,4-dihydroxyphenylacetic acid (DOPAC).[ 17 ]

Given this complex sequence, dopamine modulation can occur at various levels, such as the entire neuron, its projections or neural circuits of the nervous system. In addition, during DA synthesis (transcriptional, translational and post-translational regulation), synaptosomal packaging (VMAT regulation, vesicle transport into the synapse), DA release (neuronal depolarization, calcium signaling, vesicle fusion) and through reuptake and metabolism through the regulation of the corresponding enzymes and their spatial localization relative to their substrate. [ 18 ]

As previously stated, the systemic action of DA depends on various receptors (D1, D2, D3, D4, and D5) and alpha- and beta-adrenergic receptors. These G-coupled receptors are commonly grouped as D1 or D2, primarily based on their traditional biochemical functions indicating that dopamine can modulate adenylate cyclase activity.[ 19 ] However, based on their molecular structure, biochemical properties, and pharmacological functions, DA receptors are further classified as D1-class (D1 and D5) or D2-class (D2, D3, D4).[ 20 ],[ 21 ]

Activation of D1 receptors on smooth muscle, the proximal renal tubule, and the cortical collecting duct increases diuresis.[ 22 ] D2 receptors are located presynaptically on the renal nerves, glomeruli, and adrenal cortex. Activation of these nerves results in decreased renal excretion of sodium and water.[ 23 ] Apomorphine is a DA receptor agonist and may have similar activation at these DA receptors.[ 24 ] Adrenergic receptors also bind DA, increasing arterial smooth muscle contraction and cardiac sinoatrial node conduction, accounting for its therapeutic benefits to the heart.

Although the blood-brain barrier specifically limits the transfer of DA from the systemic circulation to the central nervous system, further research has led to the discovery of its central role in reward-seeking behavior, in which its transfer is markedly increased. Current research on DA includes epigenetic alterations and their involvement in a variety of psychiatric conditions, including substance abuse and addiction, schizophrenia, and attention deficit disorder.[ 25 ],[ 26 ] In general, these conditions involve disturbances in the mesolimbic and mesocortical DA pathways. One common effect of addictive drugs in the CNS is increased DA release in the striatum, which is typically associated with high locomotor activity and stereotypy. [ 27 ] The increase in DA in the striatum is the result of axonal projections arising directly from the substantia nigra pars compacta (SN) and ventral tegmental area (VTA), respectively, which project to the nucleus accumbens and amygdala.[ 28 ],[ 29 ]

Another DA circuit, the tuberoinfundibular pathway, is primarily responsible for regulating the neuroendocrine prolactin from the anterior pituitary gland, known for its role as an inducer of lactation, but also plays a minor role in water-salt homeostasis, immune response, and cell cycle regulation.[ 30 ],[ 31 ] The nigrostriatal pathway is the major pathway involved in the motor deficits observed in Parkinson's disease.[ 32 ] This pathway involves dopaminergic neurons originating in the substantia nigra (pars compacta) and projecting to the striatum via the medial forebrain bundle, synapsing with multiple neuronal populations in the putamen, caudate nucleus, globus pallidus interna (GPi), and subthalamic nucleus (STN), respectively. This elaborate network forms afferent connections from the substantia nigra to the circuit involved in motor movement, namely the basal ganglia. In the latter, DA plays a key role in the control of motor movements and the learning of new motor skills. [ 33 ]

Dosing and administration

For stimulation of the sympathetic nervous system, continuous intravenous drip administration is indicated. The half-life of dopamine in the systemic circulation is 1 to 5 minutes; thus, slower forms of administration, such as oral administration, are usually ineffective.[ 38 ]

In addition to its peripheral sympathetic effects, DA is also critical for neurological motor function in Parkinson's disease. L-DOPA is administered orally, and after absorption, a small percentage is transported to the brain where neurons use it in the basal ganglia. L-DOPA is usually co-administered with carbidopa to inhibit the peripheral effects of L-DOPA on the sympathetic nervous system. Carbidopa is a decarboxylase inhibitor that prevents the systemic conversion of L-DOPA to DA, thereby reducing common side effects such as nausea and vomiting.[ 39 ]

[ 40 ], [ 41 ], [ 42 ]

Contraindications

Intravenous dopamine is contraindicated in patients with cardiac or circulatory disease. These conditions may include ventricular arrhythmias and tachycardia, vascular occlusion, low blood oxygen, decreased blood volume, acidosis, and adrenal dysfunction resulting in high blood pressure, such as pheochromocytoma. In patients recently treated with monoamine oxidase inhibitors, DA should initially be given in fractional doses (one-tenth of the usual dose) and further effects should be closely monitored. Drugs used to treat hypertension, such as beta- and alpha-adrenergic receptor inhibitors, counteract the therapeutic effects of DA. Haloperidol also blocks the systemic effects of DA. The anticonvulsant phenytoin has been reported to cause hypotension and decrease heart rate when used with DA. On the other hand, tricyclic antidepressants increase the DA response, similar to anesthetics such as cyclopropane and halogenated. When combined with oxytocin, the use of DA can lead to chronic hypertension and can also cause cerebrovascular accidents.[ 34 ]

Side effects Dopamine

Dopamine administration can adversely affect kidney function, causing increased urination and irregular heartbeat.[ 35 ] Excessive administration can cause dangerous conditions such as cerebrovascular accidents due to increased blood pressure in the brain.[ 36 ]

As noted earlier, the neurotransmitter DA also acts in the central mesocorticolimbic pathway and plays a role in reward and fear processing, as well as in attentional focusing and executive functioning, including complex planning. While systemic dopamine does not cross the blood-brain barrier, central dopamine is implicated in sleepiness, schizophrenia, addiction, and impulse control disorders.[ 37 ] Patients with neurological diseases using high doses of L-DOPA to treat Parkinson's disease may experience such physiological changes due to dysregulation of DA in the CNS pathways.

Storage conditions

In a place protected from light.

Special instructions

Monitoring of blood pressure and urine flow is necessary - monitoring of more complex hemodynamic parameters such as cardiac output including rhythm and pulmonary wedge pressure is also recommended. It is worth noting that dopamine agonists and mimetics that penetrate the blood-brain barrier interact with neurological circuits involved in motor, executive and limbic functions, including addiction-related reward systems, impulse control mechanisms and arousal. Thus, discontinuation of DA therapy can lead to a condition called dopamine agonist withdrawal syndrome. This condition has a wide range of symptoms including anxiety, depression, panic attacks, fatigue, hypotension, nausea, irritability and even suicidal ideation. [ 43 ] Therefore, patients are advised to gradually wean themselves off these centrally acting DA agonists.

Shelf life

Shelf life is 2 years.

Dopamine deficiency

There are numerous studies that examine the role of dopamine in the participation of movements, sensorimotor functions. Accordingly, with a deficiency of dopamine in dopaminergic endings without pharmacological intervention or gene therapy, and therefore with DA depletion, defects in many of these functions are found. [ 44 ]

Excess dopamine

In this case, we need to consider such a phenomenon using an example. So, a person goes on a diet and is determined to finish what he started. But then a delicious cake comes to hand and everything ends. Thus, the person simply stops controlling himself. He needs a dose of the "happiness hormone" and it is this sweet joy that can "cause" it. So, eating one cake, then the second, the person is simply unable to stop. Thus, that very excess of dopamine occurs. There is nothing terrible about this. But it is quite difficult for a person to stop.

Ultimately, by "getting hooked" on yet another "sweetener" of life, it is simply impossible to exercise control. A person is no longer able to do this. He continues to do the same thing and thus, gets fat or worsens his health. Everything depends on what role this very hormone of happiness plays.

Dopamine can influence many aspects of conscious activity. It is necessary to reduce its level and not allow excess. But this can also be "dangerous", because reducing impulsivity can lead to damage to other equally important functions.

[ 45 ], [ 46 ], [ 47 ]

Dopamine reuptake inhibitors

Dopamine reuptake inhibitors (DRIs) are a class of drugs that act as reuptake inhibitors of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine that is not taken up by the postsynaptic neuron is blocked from reentering the presynaptic neuron. This results in increased extracellular dopamine concentrations and increased dopaminergic neurotransmission.[ 48 ]

Dopamine reuptake inhibitors are used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy due to their psychostimulant effects, and in the treatment of obesity and binge eating disorder due to their appetite suppressant effects. They are sometimes used as antidepressants in the treatment of mood disorders, but their use as antidepressants is limited given that potent DRIs have a high abuse potential and legal restrictions on their use. Lack of dopamine reuptake and increased extracellular dopamine levels have been associated with increased susceptibility to addictive behavior when dopaminergic neurotransmission is increased. The dopaminergic pathway is thought to be potent in reward centers. Many DRIs, such as cocaine, are drugs of abuse due to the rewarding effects produced by increased synaptic dopamine concentrations in the brain.

The following drugs have DRI activity and have been or are used clinically specifically for this property: amineptine, dexmethylphenidate, diphemetorex, fencamfamine, lefetamine, levofacetophenone, medifoxamine, mesocarb, methylphenidate, nomifensine, pipradrol, prolintane, and pyrovalerone. The following drugs are or have been used clinically and have only weak DRI activity that may or may not be clinically significant: adrafinil, armodafinil, bupropion, mazindol, modafinil, nefazodone, sertraline, and sibutramine.

Dopamine blockers

The expression of many unconditioned and conditioned behaviors can be impaired by D1 and D2 antagonist drugs. For example, D1 and D2 antagonists reduce locomotor activity [ 49 ], [ 50 ], [ 51 ] and rate of appetitively motivated operant behavior. [ 52 ], [ 53 ], [ 54 ], [ 55 ] However, at least one aspect of behavioral expression, the duration of behavioral acts, appears to be relatively specifically modulated by D2 receptor antagonists (relative to D1).

We have previously observed that systemic D1 receptor blockade reduces the proportion of trials in which the conditioned stimulus (CS) elicits an approach response, an effect that we did not observe following D2 receptor blockade.[ 56 ] Other studies have similarly reported that cue-response expression is impaired by D1,[ 57 ] but not D2,[ 58 ],[ 59 ] receptor blockade, although several studies have observed D2 antagonist-induced cue-response expression impairments.[ 60 ],[ 61 ]

Dopamine exchange

Do you know how dopamine is exchanged? Today, there is an active search for agents that have a dopaminergic effect. As a result of its chronic deficiency, various changes in the functional state of receptors can develop.

Long-term treatment can cause irreversible changes in dopaminergic receptors. But this does not stop the progressive degeneration of the presynaptic neuron. That is why a search was conducted for special means that could stimulate postsynaptic receptors and make them more responsive to treatment. These include dopaminergic agonists. But there are also some concerns. Thus, if dopaminergic agonists are used for a long time, this can lead to inhibition of tyrosine hydroxylase activity.

[ 62 ], [ 63 ], [ 64 ], [ 65 ], [ 66 ], [ 67 ]

Dopamine production

Scientists have proven that any activity that can bring pleasure leads to the production of the hormone of happiness. Therefore, it does not matter at all what a person does, the main thing is that it makes him happy. But, naturally, the activities should be within reasonable limits. If you exclude all joys, the level of dopamine will significantly decrease and a person can fall into depression.

It is necessary to understand that dopamine has been attributed to a type of drug addiction. Because a person who loves cakes eats them constantly to improve his mood. Which leads to other problems, such as poor health, excess weight, etc. If you take away the "joy", then depression appears and the mood worsens. Ultimately, it is a vicious circle. Therefore, you need to choose more useful activities.

The easiest and most enjoyable way to trigger the "production" of dopamine is to have sex regularly. Only if this activity really brings pleasure.

[ 68 ], [ 69 ], [ 70 ], [ 71 ]

Dopamine and schizophrenia

The origins of the dopamine hypothesis lie in two lines of evidence. First, clinical studies established that dopaminergic agonists and stimulants can induce psychosis in healthy individuals and worsen psychosis in patients with schizophrenia.[ 72 ] Second, antipsychotic drugs were found to affect the dopamine system.[ 73 ] Later, the efficacy of antipsychotics was linked to their affinity for dopamine D2 receptors, linking molecular action to clinical phenotype.[ 74 ]

Postmortem studies provided the first direct evidence of dopaminergic dysfunction in the brain and its anatomical location. They showed elevated levels of dopamine, its metabolites, and receptors in the striatum of people with schizophrenia. [ 75 ], [ 76 ] However, the studies involved patients receiving antipsychotics. Therefore, it was unclear whether the dysfunction was related to the onset or end-stage of the disorder, or indeed to the effects of antipsychotics.

[ 77 ], [ 78 ], [ 79 ], [ 80 ], [ 81 ], [ 82 ], [ 83 ], [ 84 ], [ 85 ], [ 86 ]

Dopamine and dopamine

So, there is no difference in these substances. Because in essence, they are the same. This substance is produced in the body and functions as a neurotransmitter. Simply put, it helps brain cells transmit certain messages. In common parlance, this substance is called the hormone of happiness.

The production of dopamine leads to a surge of activity, a good mood, high energy levels, as well as improved memory and attention. In fact, there are many advantages. It is worth noting that this substance can be produced under the influence of "sweeteners" of life. These can be both food and physical exercise. Simply put, what makes a person happy stimulates the production of this hormone. Therefore, you need to do more often what brings complete satisfaction.

Dopamine and dopamine are the same substance, performing the same function. It is important to maintain the level of the hormone of joy and then life will become more fulfilling.

[ 87 ], [ 88 ]

The Effect of Alcohol on the Dopamine System

Dopaminergic neurons that transmit information to the nucleus accumbens (NAc) shell are extremely sensitive to alcohol. For example, in studies in rats, alcohol administered into the blood at levels of 2 to 4 milligrams per kilogram of body weight increased dopamine release in the NAc shell and supported chronic alcohol self-administration.[ 89 ] In rats, oral alcohol consumption also stimulates dopamine release in the NAc.[ 90 ] However, this route of administration requires higher doses of alcohol to achieve the same effect than injecting alcohol directly into the blood.[ 91 ]

Alcohol-induced stimulation of dopamine release in the NAc may require the activity of another category of neuromodulators, endogenous opioid peptides. This hypothesis is supported by the observation that chemicals that inhibit the action of endogenous opioid peptides (i.e., opioid peptide antagonists) prevent the effects of alcohol on dopamine release. Opioid peptide antagonists act primarily on the region of the brain where dopaminergic neurons originate that project to the NAc. These observations suggest that alcohol stimulates endogenous opioid peptide activity, indirectly leading to activation of dopaminergic neurons. Opioid peptide antagonists may interfere with this process, thereby reducing dopamine release.

Alcohol's effects as a reinforcer: the role of dopamine

Although numerous studies have attempted to elucidate the role of dopamine in alcohol reinforcement by manipulating dopaminergic signaling, these studies do not allow any firm conclusions to be drawn.[ 92 ] However, comparing the effects of alcohol with the effects of common reinforcers such as food provides some clues about the role of dopamine in mediating alcohol reinforcement.

Pleasant foods activate dopaminergic signaling in the NAc shell, for example, by providing certain sensory (e.g., taste or flavor) stimuli. Orally administered alcohol similarly activates taste receptors, thereby increasing dopamine release in the NAc. However, unlike food, alcohol can directly alter the function of dopaminergic neurons once it reaches the brain. Accordingly, oral alcohol influences dopamine release in the NAc both through its taste properties (i.e., as a conventional reinforcer) and through its direct effects on the brain (i.e., as a drug reinforcer). Consistent with this hypothesis, two peaks of dopamine release occur in the NAc. The first peak results from the taste stimuli associated with alcohol; the second results from the effects of alcohol in the brain. As a consequence, alcohol-induced direct activation of dopaminergic signaling can enhance the motivational properties of alcohol-associated taste stimuli. As a result of this mechanism, alcohol-associated taste stimuli acquire strong incentive properties (i.e., they become motivational stimuli that motivate the drinker to seek more alcohol). Similarly, alcohol-associated appetitive stimuli (e.g., external stimuli such as the appearance of a particular brand of alcoholic beverage or the appearance of a bar) also acquire incentive properties and promote alcohol seeking and consumption. Through these complex mechanisms, alcohol-induced dopamine release activates a secondary reinforcement circuit that promotes alcohol consumption.

The Role of Dopamine in the Development of Alcohol Addiction

Dopamine release in the NAc shell may contribute to the development of alcohol dependence. Psychological dependence on alcohol develops because alcohol-related stimuli acquire excessive motivational properties that cause a strong desire to consume alcoholic beverages (i.e., craving). As a result of this strong craving, normal reinforcers (e.g., food, sex, family, work, or hobbies) lose their significance and have only a lesser influence on the drinker's behavior.

One mechanism that may be responsible for the abnormal meaning associated with alcohol-related cues is the maladaptive nature of alcohol-induced upregulation of dopaminergic signaling in the NAc. As mentioned earlier, the enhanced release of dopamine in the NAc shell induced by normal reinforcers (e.g., food) rapidly leads to habituation, and repeated presentation of associated stimuli no longer elicits dopamine release. In contrast, no habituation occurs after repeated alcohol use. As a result of the persistent release of dopamine in the NAc shell in response to alcohol, alcohol-related stimuli acquire abnormal emotional and motivational meaning, leading to excessive control over the drinker's behavior. This excessive control is at the core of addiction.

[ 93 ], [ 94 ], [ 95 ], [ 96 ], [ 97 ]

Smoking and Dopamine

Tobacco use disorder is influenced by a variety of environmental and genetic factors. Environmental factors cover a wide range of cultural, social, and economic aspects. Genetic factors can be divided into two main groups: genes associated with pathways related to nicotine metabolism, which indicates how quickly someone metabolizes nicotine into cotinine, and genes associated with the reward cascade theory, which is the amount of pleasure experienced when smoking. The most important genes affecting nicotine metabolism are cytochrome P450 CYP2A6 and CYP2B6. Genes affecting the reward cascade theory include a complex network of serotonin, opioids, gamma-aminobutyric acid (GABA), and dopamine.[ 98 ]

Read about studies of dopamine candidate genes and smoking in this article.

[ 99 ], [ 100 ], [ 101 ]

How to increase dopamine?

In fact, there is nothing complicated about this process. You need to try to include in your daily plan those activities that can bring joy.

But that's not all. So, it is recommended to eat bananas every day. They contain a substance similar to dopamine. Small brown spots on the fruit contain a larger amount of this useful "substance". The diet should be filled with products containing antioxidants. They are among the free radicals that increase dopamine levels on their own. Such products include red beans, cranberries, artichokes, strawberries, plums and blueberries.

It is useful to give up decaffeinated coffee, start consuming less sugar and reduce the consumption of alcoholic beverages. It is recommended to eat a handful of almonds daily, sunflower seeds are also suitable. It is also advisable to eat sesame, it will be a great addition to any salad and sandwich containing fresh vegetables.

Dopamine in foods

Dopamine plays an important role in the human body for the coordination of body movements, motivation and reward. Information regarding the content of dopamine products is very limited, possibly due to the lack of clinical interest. Fruits of the genus Musa, such as bananas and sycamores, and the species M. Persea americana (i.e., avocado) contain high levels of dopamine. [ 102 ] In particular, dopamine levels have been detected in banana peel (700 μg/g), banana pulp (8 μg/g) and in avocado (4–5 μg/g). In plants, dopamine plays a protective role and is involved in reproductive organogenesis, ion permeability, antioxidant activity [ 103 ] and in the formation of alkaloids. [ 104 ] Interestingly, the leaves of Mucuna pruriens L. (i.e. velvet bean) have been shown to contain dopamine, [ 105 ] thus possibly participating in the well-known antiparkinsonian effects of seed-derived products. [ 106 ] Low levels have been measured in Citrus sinensis L. (i.e. orange), Malus sylvestris L. (i.e. wood apple), tomato, eggplant, spinach, peas and beans. Episodic movement disorders (i.e. side-to-side head shaking) have been reported after consumption of skim milk. The same authors attributed these effects to the high L-tyrosine content of dairy products. [ 107 ] However, a possible dopamine interaction cannot be excluded, but the literature data are insufficient.