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Schizophrenia-Like Behavior In Rats Blocked Via Glutamate

An unexpected clue from a rat model of psychosis has led National Institute of Mental Health grantees to propose a new strategy for treating schizophrenia. Scientists have known for some time that the psychosis-inducing drug PCP (phencyclidine) blocks activation of receptors for the brain messenger chemical glutamate while stimulating activation of brain dopamine systems. Current antipsychotic drugs act by reducing dopamine activity.

When Dr. Bita Moghaddam and Barbara Adams of Yale University injected rats with PCP, they expected to see glutamate activity plummet as levels of dopamine soared. Instead, they found that doses of PCP that produced psychosis-like symptoms also increased glutamate levels. The PCP-induced neurotransmitter changes were accompanied by a characteristic pattern of aberrant running and head-turning behaviors and working memory impairments in the animals, which mimics some symptoms of schizophrenia.

Might this psychotic-like behavior be prevented by quenching glutamate? To find out, the researchers targeted a glutamate receptor subtype, known to fine-tune the neurotransmitter's activity, using an experimental compound (LY354740) under development by Eli Lilly & Co. The compound attenuates and normalizes glutamate activity by stimulating these presynaptic receptors, located on nerve terminals of glutamate-secreting neurons. In rats pretreated with the Lilly compound, PCP failed to trigger the behavioral abnormalities, cognitive impairments, or glutamate increases in the prefrontal cortex.

Affecting about 1 percent of adults, schizophrenia is the most chronic and disabling mental illness. It typically begins as a psychotic episode in early adulthood, with devastating hallucinations, delusions, social withdrawal, blunted emotionality, and loss of social and personal care skills. A new generation of antipsychotic medications (clozapine, risperidone, olanzapine, etc.) has helped many patients manage their most flagrant symptom
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Contact: Jules Asher
jasher@nih.gov
(301) 443-4536
NIH/National Institute of Mental Health
28-Aug-1998


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