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The dopamine hypothesis


The Dopamine Hypothesis of Schizophrenia: Version III—The Final Common Pathway

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The Dopamine Hypothesis of Schizophrenia

The dopamine hypothesis stems from early research carried out in the 1960’s and 1970’s when studies involved the use of amphetamine (increases dopamine levels) which increased psychotic symptoms while reserpine which depletes dopamine levels reduced psychotic symptoms.

The original dopamine hypothesis was put forward by Van Rossum in 1967 that stated that there was hyperactivity of dopamine transmission, which resulted in symptoms of schizophrenia and drugs that blocked dopamine reduced psychotic symptoms. [1]

DOPAMINE PRODUCTION AND METABOLISM

Dopamine is synthesised from the amino acid tyrosine. Tyrosine is converted into DOPA by the enzyme tyrosine hydroxylase.

DOPA is converted into dopamine (DA) by the enzyme DOPA decarboxylase (DOPADC).

This dopamine is packed and stored into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and stored until its release into the synapse.

Dopamine Receptors:

When dopamine is released during neurotransmission, it acts on 5 types of postsynaptic receptors (D1-D5).

A negative feedback mechanism exists through the presynaptic D2 receptor which regulates the release of dopamine from the presynaptic neuron.

 

Dopamine Breakdown

Any excess dopamine is also ‘mopped up’ from the synapse by Dopamine transporter (DAT) and stored in the vesicles via VMAT2.

Dopamine is broken down by monoamine oxidase A (MAO-A), MAO-B and catechol-o-methyltransferase (COMT).

Learning points:

  1. Tyrosine hydroxylase is the rate-limiting step in the production of dopamine. Its expression is significantly increased in the substantia nigra of schizophrenia patients when compared to normal healthy subjects. [2]
  2. Carbidopa is a peripheral DOPA-decarboxylase inhibitor co-administered with levodopa. Carbidopa prevents the conversion of levodopa to dopamine in the periphery, thus allowing more levodopa to pass the blood-brain barrier to be converted into dopamine for its therapeutic effect.
  3. Methamphetamine increases extracellular dopamine by interacting at vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine uptake and promote dopamine release from synaptic vesicles, increasing cytosolic dopamine available for reverse transport by the dopamine transporter (DAT).
  4. Valbenazine a highly selective VMAT2 inhibitor has been approved by the FDA for the treatment of tardive dyskinesia.
  5. There is compelling evidence that presynaptic dopamine dysfunction results in increased availability and release of dopamine and this has been shown to be associated with prodromal symptoms of schizophrenia. Furthermore, dopamine synthesis capacity has also been shown to steadily increase with the onset of severe psychotic symptoms. [3] , [Howes & Shatalina, 2022]

  1. Dopaminergic transmission in the prefrontal cortex is mainly mediated by D1 receptors, and D1 dysfunction has been linked to cognitive impairment and negative symptoms of schizophrenia. [4]
THE 4 DOPAMINE PATHWAYS IN THE BRAIN

 

1.The Mesolimbic Pathway

  • The pathway projects from the ventral tegmental area (VTA) to the nucleus accumbens in the limbic system.
  • Hyperactivity of dopamine in the mesolimbic pathway mediates positive psychotic symptoms. The pathway may also mediate aggression.
  • The mesolimbic pathway is also the site of the rewards pathway and mediates pleasure and reward. Antipsychotics can block D2 receptors in this pathway reducing pleasure effects. This may be one explanation as to why individuals with schizophrenia have a higher incidence of smoking as nicotine enhances dopamine in the reward pathway (self-medication hypothesis)
  • Antagonism of D2 receptors in the mesolimbic pathway treats positive psychotic symptoms.
  • There is an occupancy requirement with the minimum threshold at 65% occupancy for treatment to be effective. Observations support this relationship between D2-receptor occupancy and clinical response that 80% of responders have D2-receptor occupancy above this threshold after treatment. [5]

2.The Mesocortical Pathway

  • Projects from the VTA to the prefrontal cortex.
  • Projections to the dorsolateral prefrontal cortex regulate cognition and executive functioning.
  • Projections into the ventromedial prefrontal cortex regulate emotions and affect.
  • Decreased dopamine in the mesocortical projection to the dorsolateral prefrontal cortex is postulated to be responsible for negative and depressive symptoms of schizophrenia.
  • Nicotine releases dopamine in the mesocortical pathways alleviating negative symptoms (self-medication hypothesis).

3.The Nigrostriatal Pathway

  • Projects from the dopaminergic neurons in the substantia nigra to the basal ganglia or striatum.
  • The nigrostriatal pathway mediates motor movements.
  • Blockade of dopamine D2 receptors in this pathway can lead to dystonia, parkinsonian symptoms and akathisia.
  • Hyperactivity of dopamine in the nigrostriatal pathway is the postulated mechanism in hyperkinetic movement disorders such as chorea, tics and dyskinesias.
  • Long-standing D2 blockade in the nigrostriatal pathway can lead to tardive dyskinesia. 

4.The Tuberoinfundibular (TI) Pathway

  • Projects from the hypothalamus to the anterior pituitary.
  • The TI pathway inhibits prolactin release.
  • Blockade of D2 receptors in this pathway can lead to hyperprolactinemia which clinically manifests as amenorrhoea, galactorrhoea and sexual dysfunction.
  • Long-term hyperprolactinemia can be associated with osteoporosis.

Conceptualisation of Schizophrenia

Based on the above understanding, schizophrenia is best conceptualised as a complex entity which involves multiple pathways.

In clinical practice, there can be a disproportionate focus on positive psychotic symptoms.

It is however, important to recognise that affective (e.g depressive), negative and cognitive symptoms are a core part of schizophrenia and should be taken into account in treatment.

The aim of treatment, thus, is to modulate treatment creating a balance between effectiveness and reduction of side effects.

The balance is achieved by optimal dopamine blockade in the mesolimbic pathway while preserving (or enhancing) dopamine transmission in the other pathways.

DOPAMINE AND SCHIZOPHRENIA

The dopamine hypothesis of schizophrenia has moved from the dopamine receptor hypothesis (increased dopamine transmission at the postsynaptic receptors) to a focus on presynaptic striatal hyperdopaminergia.

According to Howes and Kapur-

This hypothesis accounts for the multiple environmental and genetic risk factors for schizophrenia and proposes that these interact to funnel through one final common pathway of presynaptic striatal hyperdopaminergia.

In addition to funneling through dopamine dysregulation, the multiple environmental and genetic risk factors influence diagnosis by affecting other aspects of brain function that underlie negative and cognitive symptoms. Schizophrenia is thus dopamine dysregulation in the context of a compromised brain. [6]

Read more on the molecular imaging of dopamine abnormalities in schizophrenia. 

Clinical Implications

The hypothesis that the final common pathway is presynaptic dopamine dysregulation has some important clinical implications. Firstly, it implies that current antipsychotic drugs are not treating the primary abnormality and are acting downstream. While antipsychotic drugs block the effect of inappropriate dopamine release, they may paradoxically worsen the primary abnormality by blocking presynaptic D2 autoreceptors, resulting in a compensatory increase in dopamine synthesis.

This may explain why patients relapse rapidly on stopping their medication, and if the drugs may even worsen the primary abnormality, it also accounts for more severe relapse after discontinuing treatment. This suggests that drug development needs to focus on modulating presynaptic striatal dopamine function, either directly or through upstream effects. [6]

Concept of Salience

Usually, dopamine’s role is to mediate motivational salience and thereby gives a person the ability to determine what stimulus grabs their attention and drives the subsequent behaviour.

The salience network consists of the Anterior Cingulate Cortex (ACC), insula and the amygdala.

Schizophrenia is associated with an aberrant attribution of salience due to dysregulated striatal dopamine transmission.

Dysregulation of the dopamine system ultimately leads to irrelevant stimuli becoming more prominent which provides a basis for psychotic phenomena such as ideas of reference, where everyday occurrences may be layered with a with a heightened sense of bizarre significance.  Furthermore, this misattribution of salience can lead to paranoid behaviour and persecutory delusions. [7]

A stimulus, even if initially lacking inherent salience, once paired with dopaminergic activity, maintains the ability to evoke dopaminergic activity over time.

This suggests that in psychosis, once an environmental stimulus has been highlighted by aberrant dopamine signalling, it may maintain its ability to trigger dopaminergic activity, potentially cementing its position in a delusional framework, even if the system subsequently returns to normal function. [McCutcheon, et al, 2019]

LIMITATIONS OF THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA

Current research shows that one-third of individuals with schizophrenia do not respond to non-clozapine antipsychotics despite high levels of D2-receptor occupancy.

Furthermore, a study using tetrabenazine (used as augmentation) which depletes presynaptic dopamine was not found to be effective in augmenting a clinical response in schizophrenia. [8]

Therefore, for a significant number of patients with schizophrenia, the basis of their symptoms is either unrelated to dopaminergic dysfunction or is associated with something more than just dopamine excess.

Alternatively, this could also mean that for some patients with schizophrenia there might be a non-dopaminergic sub-type of schizophrenia.

The current dopamine hypothesis of schizophrenia does not adequately explain the cognitive and negative symptoms. Current treatments which modulate dopamine transmission have only modest effects in improving these symptoms.

It has taken two decades for the dopamine hypothesis to evolve and reach its current state. More recent evidence shows another neurotransmitter, glutamate playing an essential role in schizophrenia.

The future likely holds a lot more secrets about schizophrenia which should unravel with the advances in understanding the brain.

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Dopamine theory of schizophrenia

dopamine (she or catecholamine) hypothesis pays special attention attention to dopaminergic activity in the mesolimbic brain paths.

Has been put forward the so-called "dopamine theory" schizophrenia" or "dopamine hypothesis"; according to one of its versions, patients schizophrenia learn to receive pleasure, concentrating on thoughts, causing the release of dopamine and overtax their "system" encouragement”, damage to which and cause symptoms of the disease. Among supporters of the "dopamine hypothesis" There are several different streams but in general, it connects productive symptoms of schizophrenia with disturbances in dopamine systems brain. The "dopamine theory" was very popular, but its influence in our time weakened, now many psychiatrists and schizophrenia researchers do not support this theory, considering it too simplified and unable to fully explain schizophrenia. This revision is partly contributed to the emergence new ("atypical") antipsychotics, which, when similar to the old drugs efficiency have a different spectrum effects on neurotransmitter receptors. nine0003

Primary defect dopaminergic transmission in schizophrenia could not be installed because functional assessment of dopaminergic system researchers received various results. Determination results levels of dopamine and its metabolites in blood, urine and cerebrospinal liquids turned out to be inconclusive due to a large amount of these biological environment, which leveled the possible changes associated with limited dysfunction of the dopaminergic system.

Numerous attempts to confirm this hypothesis before were aimed at determining in the cerebrospinal fluid of patients main product of dopamine metabolism - Homovanillic acid. However the vast majority of researchers failed to find significant the more specific changes in the content of homovanic acid in cerebrospinal fluid of patients. nine0003

Consideration schizophrenia as a disease associated with dysregulation in dopamine system required to measure the activity dopamine-p-hydroxylase enzyme, converting dopamine to norepinephrine. Decreased activity of this key enzyme in the brain tissue of patients schizophrenia may be the cause accumulation of dopamine and a decrease in the level norepinephrine in tissues. Such data could significantly confirm dopamine the schizophrenia hypothesis. It's an assumption checked in studies of the level dopamine p-hydroxylase in the spinal cord fluids of patients and study autopsy material (brain tissue). The content and activity of dopamine-(3-hydroxylase had no significant differences in compared with control studies. nine0003

Study results activity of these enzymes and the corresponding substrates in peripheral blood patients do not bring us closer to understanding the role of the dopaminergic systems of the brain in the pathogenesis of psychosis. The fact is that fluctuations in activity and the level of specific dopamine system enzymes like dopamine itself, on the periphery is not reflect the states of the same systems on brain level. Moreover, changes levels of dopamine activity in the brain get a physiological expression only when they occur strictly defined brain structures (striatum region, limbic system). As a result, the development of dopamine hypothesis has methodological limitations and cannot follow the path of measurement content of dopamine and related compounds in peripheral blood and urine of the mentally ill. nine0003

In a few work on a posthumously taken brain tissues of patients tried to study the condition dopamine system. Was established dopamine hypersensitivity receptors that are affinity for 3N-apomorphine, in the limbic region and striatum of the brain of patients with schizophrenia. However, strong evidence is needed. that this hypersensitivity (increase in the number of receptors) is not a consequence of drug induction, i.e. not caused by chronic administration of psychotropic compounds examined patients. nine0003

Some researchers have tried to confirm dopamine hypothesis of schizophrenia by measurement of the hormone prolactin in the blood plasma of patients before and during treatment with neuroleptics. Selection prolactin from the pituitary gland is regulated dopamine system of the brain, hyperactivity which should lead to increase in its content in the blood. However noticeable changes in prolactin levels in patients not treated with psychotropic drugs were not noted, and the examination treated patients gave inconclusive and conflicting results. nine0003

Thus, a number pharmacological and biochemical data points to a link between development mental disorders and change functions of the dopamine system in the brain synaptic and receptor levels. However, indirect methods of checking dopamine hypothesis of schizophrenia did not give positive results. Tem However, all of these approaches can be insufficiently adequate to study mechanisms of dopamine disruption brain systems. For example, if psychosis-causing changes in dopamine activities are localized only in such isolated brain structures limbic region, then all modern methods for determining this activity in biological fluids (even in cerebrospinal fluid) will be unsuitable for proof fact. Acceptability of the dopamine hypothesis to explain the nature of schizophrenia finally established with the advent more sensitive methods and adequate approaches to the study of chemical disorders at the level of the human brain. nine0003

a survival guide for those who often do not see the white line"

Approximately 45 million people worldwide suffer from bipolar disorder. It manifests itself in extreme mood swings (from euphoria to depression) and seriously complicates life. Between 25 and 50 percent of people with bipolar disorder have attempted suicide. The causes and mechanisms of development of bipolar disorder are not yet very clear to scientists, but doctors already understand how to help people with it live a normal life. In the book "Bipolar Disorder: A Survival Guide for Those Who Often Do Not See the White Stripe" (published by "AST"), journalist Maria Pushkina and psychiatrist Evgeny Kasyanov tell how bipolar disorder looks from the inside and from the outside, as well as what can be done to maintaining a balance between extreme emotional states. We invite you to read a fragment about what science thinks about the causes of bipolar disorder. nine0003

It's all about dopamine

Traditionally, scientists explained mania and depression by an imbalance in the systems of neurotransmitters 1 : serotonin, norepinephrine and dopamine.

However, in practice, everything turned out to be more complicated.
The invention of antidepressants that act on serotonin and norepinephrine made a splash. They perfectly leveled the mood of patients with "typical" unipolar depression. This discovery was later rightly called the psychopharmacological revolution .

But when antidepressants were used to treat bipolar patients, this led to very undesirable consequences - the development of mania and mixed states. What's more, people with bipolar disorder have been found to respond better to lithium and antipsychotics, especially when they are manic.

Scientists began to understand that bipolar disorder has a slightly different nature. Over the past four decades, the main hypothesis explaining the mechanism of bipolar disorder has remained dopamine hypothesis 2 .

2

Ashok A.H.

Marques T.R.

The latest research confirms that mania is based on increased activity of dopamine receptors in the brain and subsequent hyperactivation of the "reward" system. Scientists have even managed to induce manic behavior in lab mice by artificially activating their dopamine neurons.

Reward system is an ingenious invention of evolution. These are brain structures that "reward" us with positive emotions and a sense of pleasure for successful actions, thus literally controlling our behavior. As a result, we tend to repeat these actions over and over again.

Researchers have found that bipolar depression increases levels of a protein that transports dopamine in the striatum, the area of ​​the brain responsible for the "reward" system. Because of this, the level of dopamine decreases, which is what we see in depression. It is the lack of dopamine that is responsible for anhedonia - the loss of the ability to enjoy what used to please you. nine0003

There is a hypothesis of hypersensitivity to reward in bipolar disorder. According to her, people who are predisposed to this disease have a particularly sensitive reward system. She reacts to the achievement of the goal and encouragement especially sharply, literally with stormy delight. Which, accordingly, encourages bipolar people to act even more actively, to strive for ever new achievements. This is how hypomanic and manic behavior occurs.

The hypersensitive reward system reacts with a vengeance to negative events. Therefore, the displeasure and decrease in motivation after failures in people with bipolar disorder will be stronger than in those around them. As a result, depressive symptoms develop. nine0003

However, it must be understood that the dopamine hypothesis is still only a hypothesis, that is, an assumption that is not yet sufficiently substantiated to base treatment strategies for bipolar disorder on it.

What do hormones have to do with it?

Many scientists believe that neurotransmitter imbalances in bipolar disorder are just the tip of the iceberg. There are hypotheses that explain the symptoms of other failures in the endocrine system. For example, violations of the "stress hormones" produced by the hypothalamus and pituitary gland, and the adrenal glands. nine0003

Depression is known to increase levels of corticotropin-releasing hormone and cortisol produced in the adrenal glands. Corticotropin-releasing hormone is called "the conductor of the stress symphony". It is he who triggers the mechanism of reaction to stress in the brain and then throughout the body. At the same time, the level of another stress hormone, cortisol, rises.

When the increase in the level of these hormones is short-term, the body does not suffer: evolution has adapted us to it. But if it happens for a long time (as with depression, for example), the consequences can be catastrophic: cortisol literally kills neurons in the areas of the brain responsible for thinking and memory - in the cerebral cortex and hippocampus. Perhaps this is how the weakening of cognitive abilities occurs in bipolar disorder.

However, elevated levels of stress hormones are much more common in unipolar depression than in bipolar disorder. Moreover, often in bipolar depression, the levels of stress hormones are no different from those in healthy people.

Biological clock disease

Another area of ​​research is the study of circadian rhythm disturbances (“biological clock”) in bipolar disorder.

Our brain systems that regulate circadian rhythms affect neurotransmitters - the same dopamine, serotonin and norepinephrine, the imbalance of which is associated with mood disorders. In particular, the "sleep hormone" melatonin is synthesized from serotonin at nightfall.

Mutations in circadian genes may make a person more susceptible to mood disorders, and then the person exacerbates this situation with disrupted daily routines and lack of sleep. nine0003

Everyone has probably heard that stress is bad for sleep. The fact is that the stress hormone already known to you (corticotropin-releasing hormone) suppresses the activity of all sleep centers in our brain. Evolution has thus prepared us to stay awake in times of danger.

But a depressed person experiencing chronic stress is literally deprived of sleep by this evolutionary invention.

Circadian rhythm disorders can also explain the dependence of bipolar episodes on seasons. According to a study by Fellinger M. and colleagues, the number of hospitalizations due to mania in men peaked in June, and in women in September. The number of hospitalizations due to depression for women turned out to be maximum in November (no such dependence was observed in men). With a mixed state, women were most often admitted to hospitals in June (in men, the relationship of mixed episodes with the seasons was also not found). nine0003

For information on how to restore circadian rhythms and beat insomnia, read the Bipolar Life Basics section.

BAD and hunger

Another interesting observation is related to leptin, a hormone produced by adipose tissue. Leptin is responsible for feeling full. Its synthesis is also associated with circadian rhythms. Abnormal levels of this hormone may explain the increased appetite in atypical depression.

As we can see, there are still more blank spots in the neurobiology of bipolar disorder than clear answers. Science, of course, does not stop there. Current research into affective disorders is focused on synapses (connections between neurons) and plasticity (that is, the ability to change) in brain regions involved in the regulation of emotions, memory, sleep, and even smell - the prefrontal cortex, the hippocampus, and the amygdala. Perhaps over time they will answer the question of what exactly is wrong with the bipolar brain. nine0003

Abnormal brain

Until the middle of the 20th century, doctors did not have safe tools for studying the brain, and therefore one could only guess about the causes of manias and depressions. Post-mortem autopsies showed no brain anomalies.

Modern science has high-tech methods of neuroimaging - that is, the study of the structure and functions of the brain using images. Thanks to such methods as MRI, CT, PET 3 , it was possible to detect certain disorders in the structure of the brain of bipolar people. nine0003

The ENIGMA Bipolar Working Group 4 reviewed over 6,500 MRI scans (the largest MRI scan of the gray matter to date!) and found the following abnormalities:

4

900.54

People with bipolar disorder had less gray matter in the frontal, temporal and parietal areas of both hemispheres of the brain.

Gray matter is the operational center of the body. It allows us to think, move, perceive the world around us. nine0003

The areas most severely affected were the left frontal operculum (the area between the anterior ascending branch of the lateral sulcus and the inferior part of the precentral sulcus), the left fusiform gyrus, and the left median frontal cortex. This phenomenon is called cortical thinning .

It has been observed that the longer the disease lasted, the thinner the cortex in the frontal, medial parietal and occipital areas of the brain.

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