Glutamate hypothesis of schizophrenia
Encyclopedia
The 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 receptor
s. While thought to be more proximal to the root causes of schizophrenia
, it does not negate the dopamine hypothesis
, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.
Like dopamine hypothesis, the development of the glutamate hypothesis developed from the observed effects of mind-altering drugs. However, where dopamine agonists can mimic positive symptoms with significant risks to brain structures during and after use, glutamate antagonists, such as PCP
and ketamine
, mimic some positive and negative symptoms with less brain harm.
Unfortunately, the typical antipsychotics are known to have significant risks of side effects that can increase over time, and only show clinical effectiveness in reducing positive symptoms. Additionally, although newer atypical antipsychotics can have less affinity for dopamine receptors and still reduce positive symptoms, they may not adequately reduce negative symptoms.
and PCP
were observed to produce significant similarities to schizophrenia. Ketamine produces more similar symptoms (hallucinations, withdrawal) without observed permanent effects (other than ketamine tolerance). PCP however is less representative symptomatically, but does appear to cause brain structure changes seen in schizophrenia. No drug has been found to induce schizophrenic symptoms completely, nor has been able to mimic developmental abnormalities.
of the drug LY2140023 has shown potential for treating schizophrenia
without the weight gain and other side-effects associated with conventional anti-psychotics. This drug acts as a selective agonist
at metabotropic
mGluR2
and mGluR3
glutamate receptors (the mGluR3 gene has previously been associated with schizophrenia.).
Studies of glycine
(and related co-agonists at the NMDA receptor
) added to conventional anti-psychotics have also found some evidence that these may improve symptoms in schizophrenia.
post-synaptic receptor genes are deleted, the dendritic spines
of glutamate neurons initially grow, but break down during later development. It was found that symptomic similarities to the disease matched schizophrenia upon expression.(symptoms such as disturbed social function, inability to adapt to predictable future stressors) This parallels the time delay for symptoms setting in with schizophrenic humans who usually appear to show normal development until early adulthood.
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s. While thought to be more proximal to the root causes of schizophrenia
Causes of schizophrenia
The 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...
, it does not negate the dopamine hypothesis
Dopamine hypothesis of schizophrenia
The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model attributing 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...
, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.
Like dopamine hypothesis, the development of the glutamate hypothesis developed from the observed effects of mind-altering drugs. However, where dopamine agonists can mimic positive symptoms with significant risks to brain structures during and after use, glutamate antagonists, such as PCP
Phencyclidine
Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
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...
, mimic some positive and negative symptoms with less brain harm.
Current State of Schizophrenia Treatment
Schizophrenia that is unmanagable by lifestyle changes (like reducing stress or stopping drug habits) is now treated by medications known as antipsychotics (or neuroleptics) that typically reduce dopaminergic activity because too much activity has been most strongly linked to positive symptoms (thing which should not be there, such as hallucinations or a paranoid delusion).Unfortunately, the typical antipsychotics are known to have significant risks of side effects that can increase over time, and only show clinical effectiveness in reducing positive symptoms. Additionally, although newer atypical antipsychotics can have less affinity for dopamine receptors and still reduce positive symptoms, they may not adequately reduce negative symptoms.
Glutamate antagonists
KetamineKetamine
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...
and PCP
Phencyclidine
Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
were observed to produce significant similarities to schizophrenia. Ketamine produces more similar symptoms (hallucinations, withdrawal) without observed permanent effects (other than ketamine tolerance). PCP however is less representative symptomatically, but does appear to cause brain structure changes seen in schizophrenia. No drug has been found to induce schizophrenic symptoms completely, nor has been able to mimic developmental abnormalities.
Possible glutamate based treatment
An early clinical trial by Eli LillyEli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
of the drug LY2140023 has shown potential for treating 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...
without the weight gain and other side-effects associated with conventional anti-psychotics. This drug acts as a selective 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...
at metabotropic
Metabotropic receptor
Metabotropic receptor is a subtype of membrane receptors at the surface or in vesicles of eukaryotic cells.In the nervous system, based on their structural and functional characteristics, neurotransmitter receptors can be classified into two broad categories: metabotropic and ionotropic receptors...
mGluR2
Metabotropic glutamate receptor 2
Metabotropic glutamate receptor 2 is a protein that in humans is encoded by the GRM2 gene.-PAMs:The development of subtype-2-selective positive allosteric modulators experienced steady advance in recent years...
and mGluR3
Metabotropic glutamate receptor 3
Metabotropic glutamate receptor 3 is a protein that in humans is encoded by the GRM3 gene.-Ligands:Though truly mGluR3 selective agents still await their discovery, mixed mGluR2/3 ligands with selectivity over other mGluR-subtypes are known...
glutamate receptors (the mGluR3 gene has previously been associated with schizophrenia.).
Studies of glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
(and related co-agonists at the NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
) added to conventional anti-psychotics have also found some evidence that these may improve symptoms in schizophrenia.
Animal Models
A research done on mice in early 2009 has shown that when the neuregulin-1\ErbBErbB
The ErbB protein family or epidermal growth factor receptor family is a family of four structurally related receptor tyrosine kinases. The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: Erythroblastic Leukemia Viral Oncogene...
post-synaptic receptor genes are deleted, the dendritic spines
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...
of glutamate neurons initially grow, but break down during later development. It was found that symptomic similarities to the disease matched schizophrenia upon expression.(symptoms such as disturbed social function, inability to adapt to predictable future stressors) This parallels the time delay for symptoms setting in with schizophrenic humans who usually appear to show normal development until early adulthood.
See also
- SchizophreniaSchizophreniaSchizophrenia 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...
- AntipsychoticAntipsychoticAn 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...
- Dopamine hypothesis of schizophreniaDopamine hypothesis of schizophreniaThe dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model attributing 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...
- Glutamate
- Typical antipsychoticTypical antipsychoticTypical antipsychotics are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis...
- Atypical antipsychoticAtypical antipsychoticThe 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...
External links
- Glutamate Hypothesis of Schizophrenia By Bita Moghaddam