Researchers interested in the treatment of schizophrenia and dementia have clarified how antipsychotic drugs work — by targeting two receptors at the surface of cells in the brain, according to a new study.
In an earlier, related study, researchers had shown that two brain receptors — which bind the neurotransmitter signals serotonin and glutamate at the outside of the cell — form a complex in the areas of the brain that malfunction in schizophrenic patients.
The team has now developed a metric that may help determine the effectiveness of antipsychotic drugs and advance drug design. The new study fills a gap in knowledge as researchers previously did not understand how this receptor complex was connected to the phenotype of schizophrenia.
The new study shows that there is a defect in the connection between the complex of the two receptors and the schizophrenic phenotype in how the serotonin and glutamate signals get interpreted at the inside of the cell, a process referred to as signaling.
It also shows how antipsychotic drugs used to treat patients work to correct such a defect in the brain, researchers say.
“Not only have we learned how antipsychotics drugs are effective, but we have also found that the signaling through this receptor complex is critical to how these anti-psychotics work,” said the study’s principal investigator Diomedes E. Logothetis, Ph.D., chair of the VCU School of Medicine’s Department of Physiology and Biophysics.
According to Logothetis, the most common cellular targets for drugs are G protein-coupled receptors, such as the ones that were examined in this study. Using cell and animal models, they found that the receptors signal very differently when they are together as a complex than when they are apart.
The metric developed by the team could be used to screen new drugs and determine their level of effectiveness or be used to assess combination therapies — putting two previously ineffective drugs together and making them more useful for some patients. Ultimately this work may translate to creating better antipsychotic drugs for patients, researchers claim.
“We can use the metric we developed to screen new drugs and determine their level of effectiveness,” Logothetis said. “We can also use the metric to assess what combinations of existing drugs will give us the ideal balance between the signaling through the two receptors of the complex.”
Logothetis said the hope is that, by using this approach, one day researchers will be able to develop a means by which high-throughput screening of drugs can be performed, as well as be able to develop more effective combinations of drugs that are able to help the one-third of schizophrenic patients who do not respond to current treatments.
Future studies will focus on further identifying the protein targets of the signaling pattern of this receptor complex and their link to schizophrenia.
The multidisciplinary team included researchers from the Virginia Commonwealth University School of Medicine, the Mount Sinai School of Medicine in New York, and the University of Maryland School of Pharmacy in Baltimore.
The new study is published online in the journal Cell.
Source: Virginia Commonwealth University