May 7, 2015

Findings reveal new target in quest to ease schizophrenia

Vanderbilt University researchers have uncovered a surprising finding that could lead to the development of new, more effective therapies for schizophrenia, which affects more than 2 million Americans.

Leaders of a team of Vanderbilt researchers investigating a possible new approach to treating schizophrenia include (front row, from left) Jerri Rook, Ph.D., Colleen Niswender, Ph.D., and Carrie Jones, Ph.D., and (back row, from left) Zixiu Xiang, Ph.D., Shaun Stauffer, Ph.D., P. Jeffrey Conn, Ph.D., and Craig Lindsley, Ph.D. (photo by Susan Urmy)

Vanderbilt University researchers have uncovered a surprising finding that could lead to the development of new, more effective therapies for schizophrenia.

More than 2 million Americans have schizophrenia. Anti-psychotic medications help control hallucinations and delusions but provide little relief of other serious symptoms, including social withdrawal and the inability to pay attention or make decisions.

For several years scientists have tried to stimulate the NMDA receptor, which binds the neurotransmitter glutamate in the brain. Blocked or impaired NMDA receptor function has been associated with schizophrenia-like symptoms, but too much activation is toxic to nerve cells.

In partnership with Janssen Pharmaceutica N.V., Vanderbilt scientists have been developing positive allosteric modulators (PAMs) of another glutamate receptor, mGlu5. PAMs are a unique class of drug-like molecules that can boost the activity of the receptor when it binds to glutamate, much like the dimmer switch in an electrical circuit.

Last week in the journal Neuron, the Vanderbilt group reported development of a specific mGlu5 PAM, VU0409551, that produces “robust antipsychotic-like and cognition-enhancing activity” in animal models independent of an increase in NMDA receptor activity.

This finding suggests a new way to relieve the symptoms of schizophrenia without causing toxic effects, said Jerri Rook, Ph.D., assistant professor of Pharmacology and the paper’s co-first author.

“It still raises a huge challenge from a drug development perspective,” added senior author P. Jeffrey Conn, Ph.D., director of the Vanderbilt Center for Neuroscience Drug Discovery. “But I think many people in the field will say this is one of the best new potential targets out there for schizophrenia.”

Previously it had been thought that mGlu5 PAMs exerted their effects by increasing NMDA receptor signaling. Unfortunately, while this approach was designed to provide relatively subtle regulation of the NMDA receptor, many mGlu5 PAMs have adverse effects which could be due to excessive NMDA receptor activity.

Conn, the Lee E. Limbird Professor of Pharmacology, said the current study sheds important new light on the relative importance of NMDA receptor modulation in mediating the beneficial effects of mGlu5 PAMs.

It also is one of the first demonstrations in an animal model of the impact of introducing “stimulus bias” to receptor signaling (the ability of a compound to selectively stimulate one signaling pathway over another), he said.

The study’s co-first author was Zixiu Xiang, Ph.D., assistant professor of Pharmacology.

Other Vanderbilt faculty contributors were Craig Lindsley, Ph.D., William K. Warren, Jr. Professor of Medicine and the drug discover center’s director of medicinal chemistry; Colleen Niswender, Ph.D., director of molecular pharmacology; Scott Daniels, Ph.D., Carrie Jones, Ph.D., Shaun Stauffer, Ph.D., Paige Vinson, Ph.D., Michael Bubser, Ph.D., and Nellie Byun, Ph.D.

Daniels is the center’s director of drug metabolism and pharmacokinetics, Jones is director of behavioral pharmacology, Stauffer is associate director of medicinal chemistry and Vinson is director of the medical center’s high-throughput screening facility.

A video summary of the paper can be found here. The study was supported in part by National Institutes of Health grants MH062646, MH074953, NS031373 and MH084659.