New Pathway Revealed for Drugs Treating Cognitive, Mental Disorders

BUFFALO, N.Y. -- In their continuing search for promising targets for treating mental disorders, a group of neuroscientists at the University at Buffalo has identified a pathway critical to the functioning of antidepressants, antipsychotic drugs and drugs for anxiety disorders.

Results of the research appeared in the Nov. 13 issue of Proceedings of the National Academy of Sciences.

The UB researchers' work focuses on the noradrenergic system in the brain's prefrontal cortex, a region responsible for many high-level functions, such as cognitive processing, working memory and control of emotions.

"Abnormal operation of the α-adrenergic system, one type of noradrenergic receptor in the prefrontal cortex, is strongly linked to many neuropsychiatric disorders, including depression, anxiety, ADHD and schizophrenia," said Zhen Yan, Ph.D., a senior author on the study, along with Jian Feng, Ph.D.

Both researchers are associate professors of physiology and biophysics in the UB School of Medicine and Bioinformatics and members of the Neurodegenerative Disease Group in UB's New York State Center of Excellence in Bioinformatics and Life Sciences.

"Many antidepressant, anti-anxiety and antipsychotic drugs target the α-adrenergic system," Yan continued. "Until now it has been unclear how α-adrenergic receptors perform the complicated functions carried out by the prefrontal cortex."

The research team revealed that a critical target of α-adrenergic receptors is the NMDA-type glutamate receptor channel, which also is a pivotal player in cognition and emotion. Glutamate is a neurotransmitter normally involved in learning and memory, but under certain circumstances it can be toxic and may cause nerve cell death in a variety of neurodegenerative disorders.

"We found that different α-adrenergic receptors regulate the activities of NMDA receptor channels by activating specific intracellular signaling cascades," said Yan. "Moreover, we have identified two important players that influence critically the regulatory effects of α-adrenergic receptors, known as RGS4 and spinophilin, which are involved in schizophrenia and depression, respectively.

"Modifying α-adrenergic signaling has been considered one of the key therapeutic actions of many current drugs," noted Yan. "To understand the functional role of α-adrenergic receptors, we needed to know their cellular targets. The NMDA receptor channel has been implicated in both normal cognitive processes and mental disorders, which makes it a potentially important target by which α-adrenergic receptors may regulate prefrontal cortex functioning.

Insights gained from this discovery eventually may provide new drug targets for various neuropsychiatric diseases, Yan said.

Wenhua Liu, Ph.D., and Eunice, Y. Yuen, Ph.D., postdoctoral associates in Yan's laboratory performed the experiments. Also contributing to the research were Patrick B. Allen from the Yale University School of Medicine, and Paul Greengard from Rockefeller University.

The work is supported by grants awarded to Yan from the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute of Aging and the National Alliance for Research on Schizophrenia and Depression.

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. The School of Medicine and Biomedical Sciences is one of five schools that constitute UB's Academic Health Center.