Dopamine hypothesis of schizophrenia
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The '''dopamine hypothesis of schizophrenia''' or the '''dopamine hypothesis of psychosis''' is a model attributing symptoms of [[schizophrenia]] (like [[psychosis|psychoses]]) to a disturbed and hyperactive dopaminergic [[signal transduction]]. The model draws evidence from the observation that a large number of [[antipsychotic]]s have DA-antagonistic effects. The theory, however, does not posit [[dopamine]] overabundance as a complete explanation for schizophrenia.
== Introduction ==
Some researchers have suggested that dopamine systems in the [[mesolimbic pathway]] may contribute to the 'positive symptoms' of schizophrenia (whereas problems with dopamine function in the [[mesocortical pathway]] may be responsible for the 'negative symptoms', such as [[avolition]] and [[alogia]].
Recent evidence on a variety of animal models of psychosis, such as sensitization of animal behaviour by [[amphetamine]], or [[phencyclidine]] (Angel Dust), or excess [[steroids]], or by removing various genes ([[COMT]], [[DBH]], [[GPRK6]], [[RGS9]], [[RIIbeta]]), or making brain lesions in newborn animals, or delivering animals abnormally by Caesarian section, all induce a marked behavioural supersensitivity to dopamine and a marked rise in the number of dopamine D<sub>2</sub> receptors in the high-affinity state for dopamine.<ref>P. Seeman et al. (2005): [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15716360&query_hl=3&itool=pubmed_DocSum Proc. Natl. Acad. Sci, USA 102:3513-3518]</ref> This latter work implies that there are multiple genes and neuronal pathways that can lead to psychosis and that all these multiple psychosis pathways converge via the high-affinity state of the [[D2 receptor]], the common target for all antipsychotics, typical or atypical.
== Discussion ==
=== Evidence for the dopamine hypothesis ===
Some of the most obvious evidence for this theory is from the effect of drugs such as [[amphetamine]] and [[cocaine]]. These drugs (and others like them) increase levels of dopamine in the brain and can cause psychosis, particularly after large doses or prolonged use. This is often referred to as '[[amphetamine psychosis]]' or 'cocaine psychosis', but may produce experiences virtually indistinguishable from the positive symptoms associated with schizophrenia. However, the acute effects of dopamine stimulants include euphoria, alertness and over-confidence; these symptoms are more reminiscent of mania than schizophrenia<ref>Jacob & Silverstone 1986</ref>. In fact, extensive reviews by Lieberman<ref>J.A. Lieberman et al. (1987): [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2884687&query_hl=1&itool=pubmed_DocSum Psychopharmacology 91: 415-433]</ref> and by Curran<ref>x.y. Curran et al. (2004): Brit. J. Psychiat. 185: 196-204 (pubmed link??!)</ref> highlight the fact that up to 75% of patients with schizophrenia have increased signs and symptoms of their psychosis upon challenge with moderate doses of [[methylphenidate]] or [[amphetamine]] or other dopamine-like compounds, all given at doses at which control normal volunteers do not have any psychologically disturbing effects.
Another important development was an accidental discovery that a group of drugs called the [[phenothiazine]]s, including [[antipsychotic]]s such as [[chlorpromazine]], [[Receptor antagonist|antagonized]] dopamine binding (particularly at [[Receptor (biochemistry)|receptors]] known as D<sub>2</sub> [[dopamine receptor]]s) and reduced positive psychotic symptoms.
This link was strengthened by experiments in 1970s which suggested that the affinity of antipsychotic drugs for the D<sub>2</sub> dopamine receptor family seemed to be inversely proportional to their therapeutic dose. This correlation between the therapeutic doses of antipsychotics and their affinities for the dopamine D2 receptor (then called the "antipsychotic/dopamine receptor") was reported by [[Philip Seeman]] in 1975<ref>P. Seeman et al. (1975): Proceedings Nat. Acad. Sci., USA 72: 4376-4380; Nature 261: 717-719 [http://www.nature.com/nature/journal/v261/n5562/abs/261717a0.html]</ref> and more recently in 2002.<ref>P. Seeman (2002): Canad. J. Psychiat. 47: 27-38 [http://www.cpa-apc.org:8080/Publications/Archives/CJP/2002/february/inReviewSeemanPhilip.asp]</ref>. There are no known exceptions to this correlation, as explained further below.
More recent experimental studies have shown that amphetamine increases the level and intensity of psychotic symptoms in people who already have, or are liable to psychosis. Some [[functional neuroimaging]] studies have also shown that, after taking amphetamine, patients diagnosed with schizophrenia show greater levels of dopamine release (particularly in the [[striatum]]) than non-psychotic individuals.
Concurrently, those treated with dopamine enhancing [[Levodopa]] for [[Parkinson's disease]] can experience psychotic side effects mimicking the symptoms of Schizophrenia.
[[genetics|Genetic]] evidence has suggested that there may be [[gene]]s, or specific variants of genes, that code for mechanisms involved in dopamine function, which may be more prevalent in people experiencing psychosis or diagnosed with schizophrenia. Dopamine related genes linked to psychosis in this way include [[COMT]], [[dopamine receptor D4|DRD4]], [[AKT1]].<!--
--><ref name="pmid18497888">{{cite journal |author=Arguello PA, Gogos JA |title=A signaling pathway AKTing up in schizophrenia |journal=[[J. Clin. Invest.]] |volume=118 |issue=6 |pages=2018–21 |year=2008 |month=June |pmid=18497888 |pmc=2391280 |doi=10.1172/JCI35931}}</ref>
=== Evidence against the dopamine hypothesis ===
Further experiments, conducted as new methods were developed (particularly the ability to use [[Positron Emission Tomography|PET]] scanning to examine drug action in the brain of living patients) challenged the view that the amount of dopamine blocking was correlated with clinical benefit. These studies showed that some patients had over 90% of their D<sub>2</sub> receptors blocked by antipsychotic drugs, but showed little reduction in their psychoses. This primarily occurs in patients who have had the psychosis for ten to thirty years. At least 90-95% of first-episode patients, however, respond to antipsychotics at low doses and do so with D2 occupancy of 60-70%. The only antipsychotic that occupies high levels of D2 receptors over 90% is [[aripiprazole]], but this drug has both a D2-blocking component and a D2-stimulating component, and it is the D2-stimulating component that "internalizes" the D2 receptors in the nerve cells of patient, making it appear that there is more D2 occupancy than is really necessary to do the job of antipsychotic action.
Just as perplexing, although dopamine inhibiting medications modify dopamine levels within minutes, the associated improvement is usually not visible for at least several days <ref>R. Thompson, ''The Brain'', ISBN: 0716714620</ref>, indicating that if nothing else, dopamine may not be ''directly'' responsible for the illness.
Similarly, a new generation of antipsychotic drugs (called the [[atypical antipsychotic]]s) were found to be just as effective as older [[typical antipsychotic]] drugs in controlling psychosis despite the fact that they blocked fewer dopamine receptors<ref>Diaz, Jaime. How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall, 1996.</ref>. More recent work, however, has shown that antipsychotic drugs such as clozapine and quetiapine are loosely bound to the dopamine D2 receptor. These drugs, therefore, come off the D2 receptors over a period of 6 to 12 hours after ingestion, explaining why PET scanning finds these drugs to occupy somewhat lower levels of D2 receptors in patients. Earlier scanning of patients at about two hours after taking clozapine or quetiapine leads to the observation that their D2 receptors are occupied to the extent of 60% or 70%, the usual therapeutic level for all the antipsychotic drugs.<ref>P. Seeman (2002): Canad. J. Psychiat. 47: 27-38 [http://www.cpa-apc.org:8080/Publications/Archives/CJP/2002/february/inReviewSeemanPhilip.asp]</ref>
The blockade of serotonin (5-HT2) receptors does not contribute either to the antipsychotic action or to alleviating the Parkinsonism that can occur at high doses of antipsychotic medication.<ref>S. Kapur et al. (1999): Amer. J. Psychiat. 156: 286-293</ref>
The excitatory neurotransmitter [[glutamate]] is now also thought to be associated with schizophrenia. [[Phencyclidine]] (also known as PCP or 'Angel Dust') and [[ketamine]], both of which block glutamate ([[NMDA]]) receptors, are known to cause psychosis closely resembling schizophrenia, further suggesting that psychosis and schizophrenia cannot fully be explained in terms of dopamine function<ref>"Daring to Think Differently about Schizophrenia". New York Times, February 24, 2008. http://www.nytimes.com/2008/02/24/business/24drug.html?_r=1&ei=5087&em=&en=6a0e8fe7296833ff&ex=1204002000&pagewanted=all&oref=slogin.</ref>. However, as reported in 2005 and mentioned above, the sensitization of animals with PCP markedly increases the animal's behavioural sensitivity to dopamine and markedly increases the number of high-affinity D2 receptors in the brain (Seeman et al., Proc. Nat. Acad. Sci., USA 102:3513-3518, 2005), implying that the multiple psychosis pathways converge through D2High, the main common target for antipsychotic medications.
Similarly, there is now a great deal of evidence to suggest there may be a number of functional and structural anomalies in the brains of some people diagnosed with schizophrenia, such as changes in [[grey matter]] density in the [[frontal lobe|frontal]] and [[temporal lobe]]s. Such changes or lesions or injuries, especially when done at an early age or in utero can lead to behavioural dopamine supersensitivity, as noted above (Seeman et al., Proc. Nat. Acad. Sci., USA 102:3513-3518, 2005). It appears, therefore, that there are multiple causes for psychosis and schizophrenia, including gene mutations, lesions, and drug abuse.
Other evidence suggests that social and environmental factors are important in explaining how either schizophrenia, or specific episodes of psychosis, are triggered. This research has led people to argue that a purely biological explanation, without reference to social, cultural or environmental factors will never fully explain such phenomena. Such socio-economic-cultural factors can become highly stressful to certain individuals, such as immigrants, markedly altering their brain chemistry, including dopamine, and can be associated with increased risk to psychotic episodes.
Psychiatrist [[David Healy (psychiatrist)|David Healy]] has argued that drug companies have inappropriately promoted the dopamine hypothesis of schizophrenia as a deliberate and calculated simplification for the benefit of drug marketing.
==See also==
*[[Glutamate hypothesis of schizophrenia]]
*[[Latent inhibition]]
== References ==
{{reflist|2}}
==External links==
*[http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=1037 cnsspectrums.com] Illustrated description.
*[http://www.schizophreniaforum.org/for/curr/AbiDargham/default.asp The Dopamine Hypothesis of Schizophrenia] - Anissa Abi-Dargham. Schizophrenia Research Forum.
[[Category:Schizophrenia]]
* [http://www.scholarpedia.org/article/Dopamine_and_schizophrenia Dopamine and Schizophrenia] - [[Philip Seeman]], [[Scholarpedia]].
[[de:Dopaminhypothese]]