Pitt Research Identifies New Target in Brain for Treating Schizophrenia

A November 3rd news release from the University of Pittsburgh:

Study published in Proceedings of National Academy of Sciences shows that orbitofrontal cortex responds to current and experimental antipsychotic drugs

PITTSBURGH- Research from the University of Pittsburgh could expand the options for controlling schizophrenia by identifying a brain region that responds to more than one type of antipsychotic drug. The findings illustrate for the first time that the orbitofrontal cortex could be a promising target for developing future antipsychotic drugs-even those that have very different mechanisms of action. The study will be published during the week of Nov. 3 in the online edition of the Journal Proceedings of National Academy of Sciences, with a print version to follow.

Bita Moghaddam [pictured], a professor in the Department of Neuroscience in Pitt's School of Arts and Sciences and the paper's lead author, found that schizophrenia-like activity in the orbitofrontal cortex - a brain region responsible for cognitive activity such as decision making - could be triggered by the two different neurotransmitters linked to schizophrenia: dopamine and glutamate. Brain activity was then normalized both by established antipsychotic medications that regulate only dopamine and by experimental treatments that specifically target glutamate.

“The orbitofrontal cortex is an area that's been somewhat neglected in schizophrenia research. This study should encourage researchers to focus on this brain region in imaging and other human studies, and also to use as a model for developing antipsychotic drugs,” Moghaddam said. “Schizophrenia appears to be caused by very diverse and sometimes rare genetic mutations. Diverse mutations can end up causing the same disease if they disrupt the function of a common group of neurons or networks of neurons. We think that the key to understanding the pathophysiology of schizophrenia and finding better treatments is to identify these networks. This data suggests that the orbitofrontal cortex may be a critical component in networks affected by schizophrenia.”

Working with UPMC neurology resident Houman Homayoun, Moghaddam first established that dopamine and glutamate could, separately, produce schizophrenia-like symptoms in the orbitofrontal cortex. They first simulated symptoms brought on by irregular neural receptors of glutamate. Studies within the last few years - including work by Moghaddam at Yale University - have shown that under-functioning glutamate receptors known as NMDA receptors can produce schizophrenia-like symptoms. Moghaddam and Homayoun found that stunting the NMDA receptors resulted in schizophrenia-like effects in the orbitofrontal cortex. The team also used a dose of amphetamine to simulate dopamine-related schizophrenia symptoms in the orbitofrontal cortex; schizophrenia is often linked to an excess of dopamine in the brain.

Moghaddam and Homayoun then tested the currently prescribed medication - a treatment developed more than 50 years ago that targets neural receptors of dopamine - and new experimental drugs that work on the glutamate system. They found that both medications normalized brain activity.

The paper can be found on the Proceedings of National Academy of Sciences' Website at www.pnas.org/content/early/recent or by contacting Morgan Kelly at 412-624-4356 (office); 412-897-1400 (cell); or by sending an email to mekelly@pitt.edu.

NIH Scientists Identify Link Between Brain Systems Implicated in Schizophrenia

An October 6th news release from the National Institutes of Health:

Scientists at the National Institutes of Health have deciphered the complex relationship between three distinct brain circuits implicated in schizophrenia. The researchers determined that one brain circuit acts through an intermediary brain circuit. The intermediary circuit acts like a volume control knob, turning up the electrical activity of still another brain circuit, or turning it down.

The finding suggests that schizophrenia could result from a malfunction anywhere in the link between these three brain circuits.

"This discovery lays the groundwork for studies that may lead to more effective treatments for schizophrenia," said Duane Alexander, M.D., director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NIH institute where the research was undertaken. "Theoretically, each of these interrelated brain mechanisms could be the focus of drug therapy."

The study was published online in the "Proceedings of the National Academy of Sciences." The research was conducted by Andres Buonanno, Ph.D., and his colleagues in the Section on Molecular Neurobiology in NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development. Other authors of the paper were: Oh Bin Kwon, Daniel Paredes, Carmen M. Gonzalez, Joerg Neddens, and Detlef Vullhorst; all of the NICHD; and Luis Hernandez, of the Universidad de los Andes, Merida, Venezuela.

To read the entire news release, click here.

New Dopamine Brain Target Discovered: Potential Breakthrough for Schizophrenia Treatment

Taken from a January 23rd press release produced by the Centre for Addiction and Mental Health:

Toronto, ON, January 23, 2007 – A team of Canadian researchers, lead by Dr. Susan George and Dr. Brian O'Dowd at the Centre for Addiction and Mental Health (CAMH), discovered a distinct dopamine signalling complex in the brain. Composed of two different types of dopamine receptors, this novel target may have a significant role in understanding and treating schizophrenia.

Published in the Proceedings of the National Academy of Sciences USA (Rashid et al., 2007), this important discovery demonstrates the existence of a Gq/11-coupled signalling unit that triggers a calcium signal, which is turned on by stimulating D1 and D2 dopamine receptors. Unlike other dopamine receptors, this novel unit will only create brain signals when both receptors are stimulated at the same time.

Using animal models. Drs. George and O’Dowd and their team identified this complex by its unique reaction to dopamine or specific drug triggers. Strikingly, stimulating this target with dopamine or specific drugs triggered a rise in calcium in the brain. As calcium has a profound effect on almost all brain function, this rise in calcium causes a cascade of events in the brain. This is the first time that a direct connection between dopamine and calcium signals has been reported.

“This distinct unit provides a novel signalling pathway through which dopamine can impact the function of brain cells”, said Dr. George. “This is significant because signalling through calcium release is a major mechanism regulating many important functions in the brain and we have provided the first direct mechanism by which dopamine can activate a calcium signal.”
This data has significant implications for schizophrenia. Research tells us that people with schizophrenia may have disordered calcium signals, and the major treatments for this disease target the dopamine system. Drs. George and O’Dowd state, "our data links these two pieces of evidence, creating better understanding of the disease and opening the door for a new generation of highly specific drugs that may help alleviate the devastating symptoms of schizophrenia."

For more information on this study view the abstract online by clicking here.