Rat Studies at Yale University School of Medicine Suggest a New Class of Medications for Treating Schizophrenia

A drug that lowers brain levels of the chemical glutamate – one of the neurotransmitters responsible for relaying messages between neurons – can reverse symptoms of a rat model of schizophrenia without apparent side effects, according to a Yale University School of Medicine study.

The research, published in the Aug. 28 issue of the journal Science, suggests a possible new class of medications that could be effective in treating schizophrenia and other psychiatric disorders, such as addiction, which are thought to be associated with abnormal glutamate-mediated neurotransmission.

The study was conduced by Bita Moghaddam, associate professor of psychiatry and neurobiology at Yale School of Medicine, and research associate Barbara W. Adams.

Rats under the influence of PCP, a hallucinogen also known as “angel dust” that causes schizophrenia-like symptoms in healthy people, developed symptoms such as frantic running, incessant head-rolling, and disturbances in memory and attention that are thought to parallel symptoms of schizophrenia in humans. By using a drug that stimulates a specific type of glutamate receptor, the Yale researchers succeeded in reversing these behavioral effects of PCP.

The promising new compound used in the Yale study, called LY354740, is being developed by Eli Lilly & Co. in Indianapolis for treating anxiety and other psychiatric disorders. The drug lowered abnormally high levels of glutamate in the PCP-treated rats by stimulating a subgroup of the metabotropic glutamate receptors (mGluRs). As glutamate levels fell, the rats showed improved working memory and reduced locomotion and head-rolling, Moghaddam reported. The drug worked at a dose that did not reduce brain levels of dopamine, an essential neurotransmitter that is the target of existing medications for schizophrenia.

“By targeting this group of glutamate receptors, we avoided the drawbacks of drugs that appear to produce undesirable side effects by interfering with the normal functioning of dopamine,” Moghaddam explained.

Researchers have been searching intensively for a drug that could replace current schizophrenia medications, such as haloperidol, which can have a number of disturbing side-effects, including uncontrollable tremors similar to those in Parkinson’s patients. Furthermore, current anti-psychotic drugs offer little relief from other schizophrenia symptoms, such as poor attention spans, jumbled thoughts and difficulty interacting with other people, according to an accompanying “News of the Week” article in the journal Science.

“The metabotropic glutamate receptors could provide important pharmaceutical targets in the treatment of psychiatric disorders associated with increased or decreased glutamate-mediated signaling between neurons,” Moghaddam said. She cautioned, however, that the drug might not have the same effect in people, and that PCP-induced symptoms in rats may not accurately reflect symptoms of schizophrenia in humans.

Research was conducted at the West Haven Veterans’ Administration Medical Center with funding from the National Institute of Mental Health.

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