Dopamine hypothesis of schizophrenia
This article needs additional citations for verification. (August 2009) |
The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model that attributes the positive symptoms of schizophrenia to a disturbed and hyperactive dopaminergic signal transduction. The model draws evidence from the observation that a large number of antipsychotics have dopamine-receptor antagonistic effects. The theory, however, does not posit dopamine overabundance as a complete explanation for schizophrenia. Rather, the overactivation of D2 receptors, specifically, is one effect of the global chemical synaptic dysregulation observed in this disorder.
Introduction
Some researchers have suggested that dopamine systems in the
In addition, significant cortical grey matter volume reductions are observed in this disorder. Specifically, the right hemisphere atrophies more, while both sides show a marked decrease in frontal and posterior volume.
Recent evidence on a variety of animal models of psychosis, such as sensitization of animal behaviour by
Discussion
Evidence for the dopamine hypothesis
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. However, the acute effects of dopamine stimulants include euphoria, alertness and over-confidence; these symptoms are more reminiscent of mania than schizophrenia.[18] Since the 2000s, several PET studies have confirmed an altered synthesis capacity of dopamine in the nigrostriatal system demonstrating a dopaminergic dysregulation.[19]
A group of drugs called the phenothiazines, including antipsychotics such as chlorpromazine, has been found to antagonize dopamine binding (particularly at receptors known as D2 dopamine receptors) and reduce positive psychotic symptoms. This observation was subsequently extended to other antipsychotic drug classes, such as butyrophenones including haloperidol. The link was strengthened by experiments in the 1970s which suggested that the binding affinity of antipsychotic drugs for D2 dopamine receptors seemed to be inversely proportional to their therapeutic dose. This correlation, suggesting that receptor binding is causally related to therapeutic potency, was reported by two laboratories in 1976.[20][21]
People with Schizophrenia appear to have a high rate of
However, there was controversy and conflicting findings over whether postmortem findings resulted from
Recent findings from meta-analyses suggest that there may be a small elevation in dopamine D2 receptors in drug-free patients with schizophrenia, but the degree of overlap between patients and controls makes it unlikely that this is clinically meaningful.
Giving a more precise explanation of this discrepancy in D2 receptor has been attempted by a significant minority. Radioligand imaging measurements involve the monomer and dimer ratio, and the 'cooperativity' model.[28] Cooperativity is a chemical function in the study of enzymes.[29] Dopamine receptors interact with their own kind, or other receptors to form higher order receptors such as dimers, via the mechanism of cooperativity.[30] Philip Seeman has said: "In schizophrenia, therefore, the density of [11C] methylspiperone sites rises, reflecting an increase in monomers, while the density of [11C] raclopride sites remains the same, indicating that the total population of D2 monomers and dimers does not change."[31] (In another place Seeman has said methylspiperone possibly binds with dimers[32]) With this difference in measurement technique in mind, the above-mentioned meta-analysis uses results from 10 different ligands.[33] Exaggerated ligand binding results such as SDZ GLC 756 (as used in the figure) were explained by reference to this monomer-dimer equilibrium.
According to Seeman, "...Numerous postmortem studies have consistently revealed D2 receptors to be elevated in the striata of patients with schizophrenia".[34] However, the authors were concerned the effect of medication may not have been fully accounted for. The study introduced an experiment by Anissa Abi-Dargham et al.[35] in which it was shown medication-free live people with schizophrenia had more D2 receptors involved in the schizophrenic process and more dopamine. Since then another study has shown such elevated percentages in D2 receptors is brain-wide (using a different ligand, which did not need dopamine depletion).[36][37] In a 2009 study, Abi-Dargham et al. confirmed the findings of her previous study regarding increased baseline D2 receptors in people with schizophrenia and showing a correlation between this magnitude and the result of amphetamine stimulation experiments.[38]
Some animal models of psychosis are similar to those for addiction – displaying increased locomotor activity.[39] For those female animals with previous sexual experience, amphetamine stimulation happens faster than for virgins. There is no study on male equivalent because the studies are meant to explain why females experience addiction earlier than males.[40]
Even in 1986 the effect of antipsychotics on receptor measurement was controversial. An article in Science sought to clarify whether the increase was solely due to medication by using drug-naive people with schizophrenia: "The finding that D2 dopamine receptors are substantially increased in schizophrenic patients who have never been treated with neuroleptic drugs raises the possibility that dopamine receptors are involved in the schizophrenic disease process itself. Alternatively, the increased D2 receptor number may reflect presynaptic factors such as increased endogenous dopamine levels (16). In either case, our findings support the hypothesis that dopamine receptor abnormalities are present in untreated schizophrenic patients."[41] (The experiment used 3-N-[11C]methylspiperone – the same as mentioned by Seeman detects D2 monomers and binding was double that of controls.)
It is still thought that dopamine mesolimbic pathways may be hyperactive, resulting in hyperstimulation of D2 receptors and positive symptoms. There is also growing evidence that, conversely, mesocortical pathway dopamine projections to the prefrontal cortex might be hypoactive (underactive), resulting in hypostimulation of D1 receptors, which may be related to negative symptoms and cognitive impairment. The overactivity and underactivity in these different regions may be linked, and may not be due to a primary dysfunction of dopamine systems but to more general neurodevelopmental issues that precede them.[42] Increased dopamine sensitivity may be a common final pathway.[28] Gründer and Cumming assert that of those living with schizophrenia and other dopaminergic related illnesses, up to 25% of these patients may appear to have dopaminergic markers within the normal range.[43]
Another finding is a six-fold excess of binding sites insensitive to the testing agent, raclopride;[44][45] Seeman said this increase was probably due to the increase in D2 monomers.[31] Such an increase in monomers may occur via the cooperativity mechanism[46] which is responsible for D2High and D2Low, the supersensitive and lowsensitivity states of the D2 dopamine receptor.[47] More specifically, "an increase in monomers, may be one basis for dopamine supersensitivity".[48]
Genetic and other biopsychosocial risk factors
.While genetics play an important role in the occurrence of schizophrenia, other biopsychosocial factors must also be taken into consideration. While focusing on the risk of schizophrenia in second generation migrants, Hennsler and colleagues relay that the dopamine hypothesis of schizophrenia may be an explanation. Some migrants who have had adverse experiences in their host country, such as racism, xenophobia, and poor living conditions, were found to have high stress levels, which increased dopaminergic neurotransmission. This increase in dopaminergic neurotransmission can be seen in the striatum and amygdala, both of which are areas in the brain that process aversive stimuli.[50]
Evidence against the dopamine hypothesis
Further experiments, conducted as new methods were developed (particularly the ability to use
Furthermore, although dopamine-inhibiting medications modify dopamine levels within minutes, the associated improvement in patient symptoms is usually not visible for at least several days, suggesting that dopamine may be indirectly responsible for the illness.[51]
Similarly, the second generation of antipsychotic drugs – the atypical antipsychotics – were found to be just as effective as older typical antipsychotics in controlling psychosis, but more effective in controlling the negative symptoms, despite the fact that they have lower affinity for dopamine receptors than for various other neurotransmitter receptors.[52] More recent work, however, has shown that atypical antipsychotic drugs such as clozapine and quetiapine bind and unbind rapidly and repeatedly to the dopamine D2 receptor.[53] All of these drugs exhibit inverse agonistic effects at the 5-HT2A/2C receptors, meaning serotonin abnormalities are also involved in the complex constellation of neurologic factors predisposing one to the self reinforcing language-based psychological deficits found in all forms of psychosis.[54][55]
The excitatory neurotransmitter
Similarly, there is now 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 and temporal lobes.[11] It appears, therefore, that there are multiple causes for psychosis and schizophrenia, including gene mutations and anatomical lesions. Many argue that other theories concerning the cause of schizophrenia may be more reliable in some cases, such as the glutamate hypothesis, GABA hypothesis, dysconnection hypothesis, and Bayesian inference hypothesis.[57]
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.
Relationship with glutamate
Research has shown the importance of
Combined networks of dopamine, serotonin, and glutamate
See also
References
- ISBN 978-0205239399.
- S2CID 29071116.
- PMID 28659691.
- S2CID 29100898.
- ^ S2CID 28889346.
- PMID 19673813.
- PMID 15978550.
- S2CID 10981981.
- S2CID 10614830.
- PMID 1981107.
- ^ PMID 15716360.
- ^ S2CID 19539621.
- PMID 9097961.
- PMID 20494336.
- S2CID 6328240.
- S2CID 30027459.
- PMID 15339823.
- S2CID 38831347.
- PMID 27206569.
- S2CID 10712301.
- S2CID 4164538.
- S2CID 20253885.
- PMID 10098918.
- S2CID 25019298.
- PMID 9796369.
- S2CID 29603849.
- PMID 3377641.
- ^ S2CID 26103252.
- ^ Safra, JE (Chairman) 2005 'Cooperativity' The New Encyclopaedia Britannica, Vol 3, Micropaedia, p 666
- ISBN 9781603273336.
- ^ a b "Dopamine Receptors: Clinical Correlates". Acnp.org. Archived from the original on 2001-02-24. Retrieved 2015-05-26.
- PMID 1358662.
- S2CID 7660844.
- PMID 10884398.
- PMID 10884434.
- S2CID 140206903.
- S2CID 11504141.
- S2CID 41440987.
- ^ "Amphetamine psychosis has been proposed as a model for some features of schizophrenia... This model of amphetamine sensitization has also been adopted as a paradigm for researchers interested in the addictive powers of drugs of abuse."
- PMID 11245696.
- S2CID 9517621.
- S2CID 540866.
- ^ ISBN 978-0-12-801829-3.
- S2CID 4372248.
- S2CID 42002535.
- PMID 4433518.
- S2CID 6146992.
- PMID 7940991.
- PMID 20485477.
- S2CID 173993492.
- ISBN 0-7167-1462-0
- ^ Diaz, Jaime. How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall, 1996.
- PMID 17251913.
- S2CID 8510590.
- PMID 16269190.
- ^ "Berenson A (24 February 2008). "Daring to Think Differently about Schizophrenia". New York Times.
- S2CID 37689272.
- PMID 10481908.
- PMID 8613804.
- PMID 17349858.
- PMID 29954475.
External links
- "CNS Spectrums". cnsspectrums.com.
- Abi-Dargham A. "The Dopamine Hypothesis of Schizophrenia". Schizophrenia Research Forum. Archived from the original on 2012-02-09. Retrieved 2008-06-08.
- .