New schizophrenia target found in the glutamate system

By Dr Matt Wilkinson

- Last updated on GMT

Related tags: Brain

US researchers have published new results that indicate the
metabotropic glutamate 5 receptor (mGluR5) could be a potential
target for new schizophrenia therapies.

Schizophrenia is a mental illness that effects more than 24m people worldwide and causes symptoms that include hallucinations, delusions, disordered thinking, movement disorders, social withdrawal and cognitive defects. Most current schizophrenia medications work by blocking the D2 receptors of dopamine neurotransmitters but these have shown somewhat limited efficacy in treating the negative and cognitive symptoms of the disorder leading to a need for improved therapies. The latest research, published in an early view article in the journal Biological Psychiatry​ by researchers from the University of Pittsburgh indicates that mGluR5 may be a valid target for schizophrenia therapies. The glutamate system is the largest neurotransmitter system in the brain and is strongly linked​ to the pathophysiology of schizophrenia as well as epilepsy and anxiety disorder. Abnormal function of the glutamate system in the prefrontal cortex and hippocampus regions of the brain have been previously linked to the cognitive deficits associated with the disorder. Eli Lilly has recently published results​ from a Phase II clinical trial showing that its latest antipsychotic drug candidate, LY2140023, acts by targeting the metabotropic glutamate 2/3 (mGlu2/3) receptor. The University of Pittsburgh researchers used a rat model of schizophrenia to test the efficacy of the mGluR5 activating drug CDPPD (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide). The schizophrenia model was generated by blocking the NMDA glutamate receptor, which leads to dysfunction of the glutamate system. The researchers found that CDPPD normalises abnormalities in prefrontal cortical function in the model leading to reduction of the behavioural abnormalities observed in untreated control models. "This work is significant because it shows that in an awake, behaving mammal (as opposed to in tissue cultures or similar preparation), activation of these receptors has a normalising effect on the spontaneous activity of prefrontal cortex neurons,"​ said Dr Bita Moghaddam, of the University of Pittsburgh and the corresponding author of the report. Interestingly, Addex Pharmaceuticals​ is currently developing a mGluR5 allosteric modulator, ADX 10059, for treating migraine-related pain and also to treat acid reflux in gastro-oesophageal reflux disease (GORD or GERD using US spelling)

Related topics: Preclinical Research

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