The dopamine hypothesis of schizophrenia

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The dopamine hypothesis of schizophrenia - dopamine hypothesis for short - is the hypothesis of the connection between the neurotransmitter dopamine and the psychotic clinical pictures of schizophrenia .

overview

As early as the 1950s, there were considerations that a change in neurotransmitters in the brain could lead to mental disorders. The administration of reserpine leads to a decrease in serotonin and adrenaline. It has been suggested that this can trigger depressive states.

In 1966, JM van Rossum hypothesized that schizophrenia could be caused by overactivity of certain dopaminergic areas of the brain . Work by Alan S. Horn & Solomon H. Snyder in 1971 appeared to confirm this; however, this was recapitulated in 1991 due to contradictions. An expanded dopamine hypothesis of schizophrenia also includes negative symptoms and assumes a simultaneous decrease in dopamine activity; Dopaminergic, not necessarily excessive, activities should therefore be the cause of schizophrenic symptoms . This takes account of the negative symptoms that remained despite the neuroleptic treatment or were even caused by it.

According to the current state of science and research, there are both findings that speak for the correctness of this hypothesis as well as those that speak against it: According to a study, the blockade of dopaminergic neurotransmissions (signal transmission in the synapse by dopamine) does not result from that the receptors are occupied with antagonists (more specifically: inactivating ligands ), but rather through a depolarization of the receptor-side membrane (post-synaptic half). Other studies have found evidence that dopaminergic stimulant adjusts the amount of dopamine receptors (DA receptors) in the synapse.

Against the dopamine hypothesis, it is argued that classic neuroleptics can cause negative symptoms or are unable to reduce them.

Even the positive symptoms of schizophrenia can only be masked by using classic neuroleptics. This also applies to the newer atypical neuroleptics . Many atypical neuroleptics also act on other neurotransmitters such as serotonin . There is even an atypical third-generation neuroleptic that has a partial agonistic effect, the active ingredient aripiprazole .

In contrast to classic neuroleptics, atypical neuroleptics also work against the negative symptoms of schizophrenia. However, treatment with neuroleptics does not cure schizophrenia, but only relieves the symptoms. This is also the case with the newer and atypical neuroleptics. Because of the abnormal dopamine activities in schizophrenia, the dopamine hypothesis has been held to this day and is still the subject of research.

History of the dopamine hypothesis

The basis of the hypothesis is the work of Arvid Carlsson & M. Lindqvist in 1963. The first version of the dopamine hypothesis was published in 1966 by JM van Rossum in his work The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. presented. He assumed and hypothesized:

"The schizophrenia could be caused by the overactivity of certain dopaminergic areas of the human brain."

In the scientific paper entitled Chlorpromazine and dopamine: conformational similarities that correlate with the antischizophrenic activity of phenothiazine drugs. investigated the two researchers AS Horn and SH Snyder the effects of the drug chlorpromazine on schizophrenic people. In this experiment, they found that this active ingredient from the group of phenothiazines blocked the signal transmission in the synapses through dopamine. Chlorpromazine in 1950 by Paul Charpentier as antihistamine developed reputierte then, however, the first classic neuroleptic (antipsychotic) in the history of medicine . The consequence of this neurotransmission blockade was that the symptoms of the schizophrenic subjects improved. More specifically, only the more noticeable plus / positive symptoms improved and the dopamine hypothesis, which was inferred from this experiment and its results, said the following:

"The blockade of the dopamine receptors causes an antipsychotic effect in schizophrenia."

This work thus confirmed the original dopamine hypothesis by van Rossum from 1966. The discovery made by AS Horn and SH Snyder in 1971 then led to a flood of scientific debates in the field of psychotic diseases. In this connection, experiments were primarily made with agonistic and antagonistic substances , in which their mode of action was observed. Since then, it has been intensively investigated how the neurotransmitters and their spectrum of activity in relation to z. B. psychotic ailments affect. This wave of research contributions has survived to this day. In 1974 the term “dopamine hypothesis” appeared for the first time in the title of a scientific study.

In 1987 the dopamine hypothesis postulated by JM van Rossum was supported by the study by JA Lieberman, JM Kane & J. Alvir. They made experiments with psychostimulant substances, which they administered to their test subjects, and these then developed typical symptoms of schizophrenia. Since the negative symptoms persisted in the schizophrenic patients despite treatment, KL Davis and others recapitulated the dopamine hypothesis put forward by van Rossum in 1991, which made hyperdopaminergia responsible for the schizophrenia. They included all relevant research results in their discussion. In this way, the positive symptoms could be treated efficiently, but the negative symptoms still persisted. They finally put forward a new and expanded dopamine hypothesis, in which they assumed a coexistence of increased and decreased dopamine activities, and then concluded:

"Schizophrenias are caused by abnormally low dopamine activities in the prefrontal cortex , which cause negative symptoms, which leads to increased dopamine activities in the mesolimbic dopamine neurons , which causes the positive symptoms."

The conclusion was that the possible coexistence of high and low dopamine activities in the schizophrenias had implications for the conceptualization of the role of dopamine in this disease. This hypothesis was well founded and implied important new treatment options for schizophrenia. In 2000 and 2003 studies then led to a link between the abnormalities of glutamate and dopamine in schizophrenia. It was determined where an increased dopamine release disrupted the glutamatergic systems, which in turn are responsible for the regulation of dopaminergic cell activities.

Basics of the dopamine hypothesis

Dopamine and its function

Structure of the neurotransmitter dopamine

Dopamine (DA) is a messenger substance from the group of neurotransmitters and functions in the gap between the nerve tracts (synapse) as a transmitter of the stimulus. Nerve cells (technically neurons) transmit stimuli via their pathways with the help of electrical transmission. The synapses are located between the individual nerve tracts. In these the neurotransmitters are released by the incoming stimulus, which then migrate to the other half of the synapses, where they dock on the receptors . With the docking to the receptors, the membrane on the side is polarized and the stimulus is passed on via a linked nerve pathway. With dopamine, this process is called “ dopaminergic neurotransmission ” or, to put it somewhat less technically, dopamine-related signal transduction (signal transmission).

There are 5 known types of receptors in dopamine. One speaks here of the D 1 to D 5 receptors and groups them as follows: “D 1 & D 5 belong to the group of D 1 receptors, while the other DA receptors D 2 , D 3 & D 4 belong to the group of D 2 receptors are counted. ”All dopamine receptor types have their specific tasks and the D 2 receptor in particular is associated with schizophrenia.

Ligands and neuroleptics

Ligands are substances that can dock on receptors; a distinction is made between activating and inactivating ligands. The activating ligands are also called agonists, and they perform a stimulus-transmitting / stimulating function on the receptor. The counterpart to the agonists are the antagonists, which do not cause a stimulus reaction at the receptor. The nature of the antagonists in the synapses is to block the receptors. Neuroleptics are special antipsychotic drugs that primarily act as antagonists in the brain. The special active ingredients have to overcome the blood-brain barrier . Then they develop their typically receptor-blocking effect.

Schizophrenia

Schizophrenias are a group of psychotic diseases that are characterized by a misunderstanding of reality. In this group of diseases, a distinction is made between the various symptoms according to two broad categories. One speaks of plus or positive and minus or negative symptoms. The plus symptoms go hand in hand with a more than real experience. Typical of plus symptoms are delusions , hallucinations and ego disorders . The minus symptoms go hand in hand with a reduced experience of reality. Symptoms such as flattening of affect , emotional and social withdrawal (anti-social), impoverishment of thought, so-called ambivalence (contradicting emotions and thoughts) and others are typical .

Development of the dopamine hypothesis

After one of the first critical discussions with the dopamine hypothesis, it developed into a model to explain schizophrenic symptoms on the basis of impaired dopaminergic neurotransmission (signal transmission). The actual dopamine hypothesis is based on the observations that the administration of chlorpromazine blocked the dopaminergic neurotransmission and the schizophrenic psychosis improved. Which led to the dopamine hypothesis that blocking dopaminergic neurotransmission was a cure for schizophrenic psychosis. Chlorpromazine has a dopamine antagonistic effect and is the first classic neuroleptic in medical history. The hypothesis was confirmed by the observations when drug substances were administered which had dopamine-agonistic and antagonistic effects, in that the schizophrenic psychoses were brought about or ameliorated.

At that time, this hypothesis was confirmed by the fact that the positive symptoms could be eliminated by classic neuroleptics. Against this dopamine hypothesis, however, the fact that negative symptoms can result from treatment with classic neuroleptics or cannot be treated. In retrospect, the dopamine hypothesis was then recapitulated in order to logically include the negative symptoms.

Explanation of the dopamine hypothesis

The dopamine hypothesis assumes that abnormal dopamine levels in the brain lead to psychotic misconceptions of reality. This is due to the falsified transmission of stimuli in the synapses due to abnormal neurotransmitter values. In the case of positive symptoms, hyperdopaminergic stimulus transmissions exaggerate the signals and there is more experience. In the case of the negative symptoms and the hypodopaminergic stimulus transmissions associated with them, the signals disappear and the experience of reality diminishes. As evidence of the excessive signal transmission, some studies indicated increased receptor densities in the dopaminergic nerve cells of the schizophrenic patients .

It has also been found that in schizophrenics there is a decrease in dopamine in the frontal areas of the brain, while there is an excess in other areas, particularly in parts of the limbic system . The finding that the dopaminergic neurons in the frontal lobe predominantly carry D 1 receptors instead of D 2 receptors and that D 2 blockers were used does not contradict this fact. The decreased dopamine activity approach is an attempt to expand the original dopamine hypothesis so that it remains valid, which is why it was recapitulated in 1991.

Findings on the dopamine hypothesis

Schizophrenia can be seen as a condition that is based on an imbalance of the neurotransmitter balance in a feedback-regulated system. Neurotransmitters are a subgroup of the messenger substances and a main role in schizophrenia plays alongside dopamine, serotonin and probably also glutamate.

A study from 1998 confirmed the previous observations of a disregulated, striatal dopamine release in schizophrenia.

The statement that homovanillic acid - a degradation product of dopamine - correlates with the positive symptoms of schizophrenia confirms the dopamine hypothesis . In the case of negative symptoms, on the other hand, according to a study from 2007 on the correlation, one assumes that negative symptoms are caused in two ways:

  1. In parallel to the treatment of plus symptoms and the typical reduction (regression) of homovanillic acid levels, minus symptoms and
  2. corresponding negative symptoms correlating to the increasing homovanillic acid values. Hence, the study concludes the existence of two classes of negative symptoms.

This study thus confirms the contradicting results of previous studies and tries to take this fact into account by means of the ambiguous classification of negative symptoms. A critical consideration of the dopamine breakdown product homovanillic acid should be considered in this case, as this metabolite cannot be used to differentiate between hypo- and hyperdopaminergies that exist at the same time. In addition, the positive symptoms are associated with hyper- and the negative symptoms with hypodopaminergies.

Furthermore, two novel mechanisms were found to regulate the production of dopamine. From this, the competitive mechanism of neuroleptics was subsequently proven and an increased number of receptors in the affected synapses - probably due to the administration of neuroleptics - was demonstrated. The receptor density in these synapses was increased, which was concluded as an adaptive reaction to the competing effects of the actual neurotransmitters and the antagonists ( ligands ) administered by the administration of neuroleptics . A source translated into German for some of these statements can be found in the article from 2000, which is a summary from the journal Der Nervenarzt . Two other studies found that the amount of dopamine receptors (DA receptors) in the synapse adjusts to the dopaminergic stimulus.

Thus, according to neuroscientific studies and research results in modern neurobiology , the dopamine hypothesis has been adequately proven, even if it only represents part of the cause of a schizophrenic condition, since dopaminergic neurotransmission is not the only cause. The dopamine hypothesis is only one component of today's neurobiological schizophrenia concepts , and it is assumed that the antipsychotic mechanism of action of neuroleptics does not result from the receptor blockage itself, but rather from the delayed depolarization block. This is due to the fact that the antipsychotic effects of neuroleptics take much longer than their absorption. Furthermore, studies from the years 2000 & 2003 confirmed the fact that an increased dopamine release in schizophrenia results in the glutamatergic neuronal systems being disrupted. These in turn regulate the dopaminergic cell activities. From this, however, the dopamine hypothesis can be linked accordingly with the glutamate hypothesis.

Combined networks of dopamine, serotonin and glutamate

A 2018 review suggested that many cases of psychosis, including those caused by schizophrenia, were due to variations in three connected networks, each based on dopamine, serotonin, and glutamate. In the end, this always caused overexcitation of dopamine D2 receptors in the ventral striatum . Faults in one system alone or in various combinations of several systems could be involved.

literature

Web links

Individual evidence

  1. ↑ Hans Bangen: History of the drug therapy of schizophrenia. Berlin 1992, ISBN 3-927408-82-4 . P. 93
  2. ↑ a b 1966 • van Rossum JM. • The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. • PMID 5954044
  3. ↑ a b 1998 • J. Nilsson • Introduction to the Medicinal Chemistry of Schizophrenia ( Memento of the original from July 16, 2006 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF; 289 kB) • Dissertation @1@ 2Template: Webachiv / IABot / dissertations.ub.rug.nl
  4. ↑ a b c 2005 • A. Abi-Dargham • The Dopamine Hypothesis of Schizophrenia By MD Anissa Abi-Dargham ( Memento of the original from February 3, 2012 on WebCite ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. • Schizophrenia Research Forum  @1@ 2Template: Webachiv / IABot / www.schizophreniaforum.org
  5. ↑ a b c 1971 • Allan Horn AS, Solomon H. Snyder • Chlorpromazine and dopamine: conformational similarities that correlate with the antischizophrenic activity of phenothiazine drugs. • PMID 5289865
  6. ↑ a b c d e f g h 1991 • Davis KL, Kahn RS, Ko G, Davidson M. • Dopamine in schizophrenia: a review and reconceptualization. • PMID 1681750
  7. ↑ 1992 • Grace AA. • The depolarization block hypothesis of neuroleptic action: implications for the etiology and treatment of schizophrenia. • PMID 1356143
  8. ↑ a b c 1981 • Creese I, Sibley DR, Leff S, Hamblin M. • Dopamine receptors: subtypes, localization and regulation. • PMID 7007083
  9. ↑ a b c 1979 • Constentin J. • [Modulation of dopaminergic receptor sensitivity in the central nervous system: important parameters in synaptic function regulation] • PMID 38958
  10. ↑ a b c 2007 • Claudia Borchard-Tuch • Schizophrenia - Bringing the soul back into harmony . • Pharmaceutical newspaper • 34/2007.
  11. ↑ a b c d 2007 • Dávila R, Zumárraga M, Basterreche N, Arrúe A, Anguiano JB. • Plasma homovanillic acid levels in schizophrenic patients: correlation with negative symptoms. • PMID 17434602
  12. ↑ a b 2004 • Steinert • 100 years of schizophrenia research - a puzzle without a picture? ( Memento of the original from May 8, 2014 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. • Slide 14/30. @1@ 2Template: Webachiv / IABot / www.zfp-web.de
  13. ↑ 2008 • Bristol Myers Squibb • Aripiprazole (Abilify® tablets, Bristol Myers Squibb) • Pharmaceutical newspaper .
  14. ↑ 2008 • Murray RM, Lappin J, Di Forti M. • Schizophrenia: from developmental deviance to dopamine dysregulation. • PMID 18499406
  15. ↑ 1963 • Carlsson A, Lindqvist M. • Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. • PMID 14060771
  16. ↑ 2004 • Kristian W. Fried • Synthesis and first in vitro and in vivo assessments of 2,3,7,8-tetrachlorophenothiazine as a dioxin analogue • Dissertation
  17. ↑ 1975 • Bürki HR, Eichenberger E, Sayers AC, White TG. • Clozapine and the dopamine hypothesis of schizophrenia, a critical appraisal. • PMID 1241920
  18. ↑ 1974 • Hökfelt T, Ljungdahl A, Fuxe K, Johansson O. • Dopamine nerve terminals in the rat limbic cortex: aspects of the dopamine hypothesis of schizophrenia. • PMID 4856104
  19. ↑ 1987 • Lieberman JA, Kane JM, Alvir J. • Provocative tests with psychostimulant drugs in schizophrenia. • PMID 2884687
  20. ↑ a b 2000 • Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Van Heertum RL, Cooper TB, Carlsson A, Laruelle M. • Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. • PMID 11032974
  21. ↑ a b 2003 • Laruelle M, Kegeles LS, Abi-Dargham A. • Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment. • PMID 14684442
  22. ↑ 1996 • Jankovic SM, Milovanovic D, Mitrovic M, Dukic-Dejanovic S. • [Dopamine receptor subtypes] • PMID 8926944
  23. ↑ 1975. • Luchins D. • The dopamine hypothesis of schizophrenia. A critical analysis. • PMID 1234325
  24. ↑ 1976 • Snyder SH. • The dopamine hypothesis of schizophrenia: focus on the dopamine receptor. • PMID 1251927
  25. ↑ a b 2007 • Frances R Frankenburg. • Schizophrenia • emedicine
  26. ↑ 2000 • A. Heinz • Dopamine hypothesis of schizophrenia - New findings for an old theory. • Published in “Der Nervenarzt”. • SpringerLink
  27. ↑ 2003 • Abi-Dargham A, Moore H. • Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia. • PMID 14580124
  28. ↑ 1990 • Carlsson M, Carlsson A. • "Chizophrenia: a subcortical neurotransmitter imbalance syndrome? • PMID 1981107
  29. ↑ 1998 • Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck CH, Charney DS, Innis RB, Laruelle M. • Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. • PMID 9619147
  30. ↑ 1991 • Grace AA. • Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. • PMID 1676137
  31. ↑ Stahl SM: Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: dopamine, serotonin, and glutamate. . In: CNS Spectr . 23, No. 3, 2018, pp. 187–191. doi : 10.1017 / S1092852918001013 . PMID 29954475 .