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 symptoms with fewer side effects. However, even the newer antipsychotics act on brain dopamine receptors, albeit more selectively, and often fail to have much effect on the "negative" cognitive and emotional symptoms of the disorder. Hence, there is a need to develop medications, such the novel glutamate compound, with different mechanisms of action.
Moghaddam and Adams report their results in the August 28 Science.
The National Institute of Mental Health (NIMH) is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services.