Dopamine hypothesis of schizophrenia
Encyclopedia
The dopamine
hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model attributing symptoms of schizophrenia
(like psychoses
) to a disturbed and hyperactive dopaminergic signal transduction
. The model draws evidence from the observation that a large number of antipsychotic
s have dopamine-receptor antagonist
ic effects. The theory, however, does not posit dopamine overabundance as a complete explanation for schizophrenia.
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
(PCP, 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 D2 receptors in the high-affinity state for dopamine.
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.
, cocaine
and similar drugs increase levels of dopamine in the brain and can cause symptoms which resemble those present in 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. Similarly, those treated with dopamine enhancing levodopa
for Parkinson's disease
can experience psychotic side effects mimicking the symptoms of schizophrenia. 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.
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.
A group of drugs called the phenothiazine
s, including antipsychotic
s 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 butyrophenone
s including haloperidol
. The link was strengthened by experiments in 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.
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, DRD4, and AKT1
.
Tobacco use is strongly associated with schizophrenia, likely through dopamine modulation by nicotinic acetylcholine receptor
s.
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 D2 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 antipsychotic aripiprazole
occupies over 90% of D2 receptors, but this drug is both an agonist
and an antagonist
at D2 receptors.
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.
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, 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. 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.
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, but may also involve other neurotransmitters.
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 lobe
s. It appears, therefore, that there are multiple causes for psychosis and schizophrenia, including gene mutations and anatomical lesions.
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.
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model attributing symptoms of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
(like psychoses
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
) to a disturbed and hyperactive dopaminergic signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
. The model draws evidence from the observation that a large number of antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
s have dopamine-receptor antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
ic 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 pathwayMesolimbic pathway
The mesolimbic pathway is one of the dopaminergic pathways in the brain. The pathway begins in the ventral tegmental area of the midbrain and connects to the limbic system via the nucleus accumbens, the amygdala, and the hippocampus as well as to the medial prefrontal cortex...
may contribute to the 'positive symptoms' of schizophrenia (whereas problems with dopamine function in the mesocortical pathway
Mesocortical pathway
The mesocortical pathway is a neural pathway that connects the ventral tegmentum to the cerebral cortex, particularly the frontal lobes. It is one of the four major dopamine pathways in the brain...
may be responsible for the 'negative symptoms', such as avolition
Avolition
Avolition is a psychological state characterized by general lack of drive, or motivation to pursue meaningful goals. A person may show little participation in work or have little interest in socializing. They may sit still for long periods of time...
and alogia
Alogia
In psychology, alogia , or poverty of speech, is a general lack of additional, unprompted content seen in normal speech. As a symptom, it is commonly seen in patients suffering from schizophrenia, and is considered as a negative symptom...
.)
Recent evidence on a variety of animal models of psychosis, such as sensitization of animal behaviour by amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
, or phencyclidine
Phencyclidine
Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
(PCP, Angel Dust), or excess steroids, or by removing various genes (COMT, DBH
Dopamine beta hydroxylase
Dopamine β-hydroxylase is an enzyme that converts dopamine to norepinephrine.DBH is a 290 kDa copper-containing oxygenase consisting of four identical subunits, and its activity requires ascorbate as a cofactor...
, GPRK6, RGS9
RGS9
Regulator of G-protein signalling 9, also known as RGS9, is a human gene, which codes for a protein involved in regulation of signal transduction inside cells...
, 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 D2 receptors in the high-affinity state for dopamine.
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.
Evidence for the dopamine hypothesis
AmphetamineAmphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
, cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
and similar drugs increase levels of dopamine in the brain and can cause symptoms which resemble those present in psychosis, particularly after large doses or prolonged use. This is often referred to as "amphetamine psychosis
Amphetamine psychosis
Stimulant psychosis is a psychotic disorder that appears in some people who use stimulant drugs. Most commonly, stimulant psychosis occurs in drug abusers who take very large doses but, in rare cases, it can also present in patients taking therapeutic doses under medical supervision...
" or "cocaine psychosis," but may produce experiences virtually indistinguishable from the positive symptoms associated with schizophrenia. Similarly, those treated with dopamine enhancing levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
for Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
can experience psychotic side effects mimicking the symptoms of schizophrenia. Up to 75% of patients with schizophrenia have increased signs and symptoms of their psychosis upon challenge with moderate doses of methylphenidate
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
or amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
or other dopamine-like compounds, all given at doses at which control normal volunteers do not have any psychologically disturbing effects.
Some functional neuroimaging
Functional neuroimaging
Functional neuroimaging is the use of neuroimaging technology to measure an aspect of brain function, often with a view to understanding the relationship between activity in certain brain areas and specific mental functions...
studies have also shown that, after taking amphetamine, patients diagnosed with schizophrenia show greater levels of dopamine release (particularly in the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
) 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.
A group of drugs called the phenothiazine
Phenothiazine
Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
s, including antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
s such as chlorpromazine
Chlorpromazine
Chlorpromazine is a typical antipsychotic...
, has been found to antagonize
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
dopamine binding (particularly at receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
known as D2 dopamine receptors
Dopamine receptor D2
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene.- Function :This gene encodes the D2 subtype of the dopamine receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity...
) and reduce positive psychotic symptoms. This observation was subsequently extended to other antipsychotic drug classes, such as butyrophenone
Butyrophenone
Butyrophenone is a chemical compound ; some of its derivatives are used to treat various psychiatric disorders such as schizophrenia, as well as acting as antiemetics....
s including haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
. The link was strengthened by experiments in 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.
Genetic
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
evidence has suggested that there may be gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
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, DRD4, and AKT1
AKT1
RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. Multiple alternatively spliced transcript variants have been found for this gene.- Function :...
.
Tobacco use is strongly associated with schizophrenia, likely through dopamine modulation by nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
s.
Evidence against the dopamine hypothesis
Further experiments, conducted as new methods were developed (particularly the ability to use PETPositron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
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 D2 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 antipsychotic aripiprazole
Aripiprazole
Aripiprazole is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression...
occupies over 90% of D2 receptors, but this drug is both an agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
and an antagonist
Antagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
at D2 receptors.
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.
Similarly, a new generation of antipsychotic drugs (called the atypical antipsychotic
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
s) were found to be just as effective as older typical antipsychotic
Typical antipsychotic
Typical antipsychotics are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis...
drugs 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. More recent work, however, has shown that atypical antipsychotic drugs such as clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
and quetiapine
Quetiapine
Quetiapine , is an atypical antipsychotic approved for the treatment of schizophrenia, and bipolar disorder....
bind and unbind rapidly and repeatedly to the dopamine D2 receptor.
The excitatory neurotransmitter glutamate is now also thought to be associated with schizophrenia. Phencyclidine
Phencyclidine
Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
(also known as PCP or "Angel Dust") and ketamine
Ketamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
, both of which block glutamate (NMDA
NMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
) receptors, are known to cause psychosis closely resembling schizophrenia, further suggesting that psychosis and schizophrenia cannot fully be explained in terms of dopamine function, but may also involve other neurotransmitters.
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
Grey matter
Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil , glial cells and capillaries. Grey matter contains neural cell bodies, in contrast to white matter, which does not and mostly contains myelinated axon tracts...
density in the frontal
Frontal lobe
The frontal lobe is an area in the brain of humans and other mammals, located at the front of each cerebral hemisphere and positioned anterior to the parietal lobe and superior and anterior to the temporal lobes...
and temporal lobe
Temporal lobe
The temporal lobe is a region of the cerebral cortex that is located beneath the Sylvian fissure on both cerebral hemispheres of the mammalian brain....
s. It appears, therefore, that there are multiple causes for psychosis and schizophrenia, including gene mutations and anatomical lesions.
Psychiatrist David Healy
David Healy (psychiatrist)
David Healy is an Irish psychiatrist who is currently a professor in Psychological Medicine at Cardiff University School of Medicine, Wales. He is also the director of North Wales School of Psychological Medicine. He became the centre of controversy concerning the influence of the pharmaceutical...
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
- Causes of schizophreniaCauses of schizophreniaThe causes of schizophrenia have been the subject of much debate, with various factors proposed and discounted or modified. The language of schizophrenia research under the medical model is scientific...
- Glutamate hypothesis of schizophreniaGlutamate hypothesis of schizophreniaThe glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors...
- Latent inhibitionLatent inhibitionLatent inhibition is a technical term used in Classical conditioning. A stimulus that has not had any significance in the past takes longer to acquire meaning than a new stimulus...
External links
- cnsspectrums.com Illustrated description.
- The Dopamine Hypothesis of Schizophrenia - Anissa Abi-Dargham. Schizophrenia Research Forum.
- Dopamine and Schizophrenia - Philip SeemanPhilip SeemanPhilip Seeman, OC, FRSC is a Canadian schizophrenia researcher and neuropharmacologist, known for his research on dopamine receptors.Born in Winnipeg, Manitoba, Seeman was raised in Montreal...
, ScholarpediaScholarpediaScholarpedia is an English-language online wiki-based encyclopedia that uses the same MediaWiki software as Wikipedia, but has features more commonly associated with open-access online academic journals....
.