Researchers from Mount Sinai School of Medicine have identified the pattern of cell signaling induced by antipsychotic drugs in a complex composed of two brain receptors linked to schizophrenia.
The discovery may allow researchers to predict the effectiveness of novel compounds for the treatment of schizophrenia and other mental disorders and may accelerate the development of antipsychotic drugs.
Until now, the molecular mechanism through which schizophrenia treatments achieve their intended antipsychotic effects was unknown. The most effective antipsychotic treatment, clozapine, was originally developed as an antidepressant and found to have antipsychotic properties. However, the use of clozapine has undesirable effects, such as glucose abnormalities and a low white blood cell count, which restrict its use.
In the study, the research teams looked at the effects of antipsychotic and hallucinogenic drugs on two brain receptors linked to schizophrenia: the glutamate mGlu2 receptor and the serotonin 5-HT2A receptor. The hallucinogenic drugs were used to induce one of the main symptoms of schizophrenia. The antipsychotic drugs increased levels of activity in the glutamate receptor and decreased levels of activity in the serotonin receptor. Introducing hallucinogens had the reverse effect. Although the ideal ratio is unknown, healthy brains have higher levels of activity in the glutamate receptor and lower levels in the serotonin receptor, while in brains of schizophrenic patients this balance is reversed.
Earlier research by the team discovered that the glutamate and serotonin receptors communicate with each other and work as a single complex switch. "In the first two phases of our research we have made important discoveries about how the receptor complex forms and how it signals, as well as how drugs alter the signaling activity to treat or cause psychosis," says Miguel Fribourg, PhD, postdoctoral fellow in the laboratory of Stuart Sealfon, MD, a Glickenhaus Professor and chairman of neurology at Mount Sinai School of Medicine. In the next phase, researchers will look for treatments that achieve the optimal balance of activity between the two receptors.
"Now that we know how current drugs affect the ratio of activity in this glutamate-serotonin receptor complex, we can try to identify or develop more effective treatments for schizophrenia that result in a healthier signaling ratio," says Javier Gonzalez-Maeso, PhD, assistant professor of Psychiatry and Neurology at Mount Sinai School of Medicine.
This study was a joint effort between several teams at Mount Sinai School of Medicine, Virginia Commonwealth University, and University of Maryland School of Pharmacy.
The findings are published in Cell.
Release Date: Nov. 23, 2011
Source: Mount Sinai School of Medicine