Scientists Uncover New Clues To Understanding Schizophrenia: New Links Discovered Between PCP And Cognitive Deficits

August 15, 1997

NEW HAVEN, Conn., Aug. 14, 1997-Scientists at Yale University School of Medicine have taken a major step toward understanding cognitive deficits in sufferers of schizophrenia. Their findings are reported in the Aug. 15, 1997 issue of the journal Science.

The Yale team's research supports the increasing view that dopamine's role in schizophrenia is more complex than biological psychiatrists had originally thought. This new study brings the scientific community one step closer to solving the mystery of schizophrenia.

Robert H. Roth, Ph.D., professor of psychiatry and pharmacology at Yale, led a neuroscience research team that studied the behavior of African green monkeys who were given repeated doses of phencyclidine (PCP), a drug that is often abused by humans. They found that PCP induces similar cognitive dysfunction as that found in patients diagnosed with schizophrenia. The team, which also studied the effects of a drug called clozapine (used to treat schizophrenia), found it to be successful in partially reversing the cognitive dysfunction in primates treated with PCP.

"The results of this study open up countless possibilities for future treatment strategies," says Dr. Roth. "It could lead to better drugs for cognitive brain dysfunction and poor response inhibition, which are common symptoms of schizophrenia."

For years, scientists have tried to gain a better understanding of schizophrenia, a brain disorder with multiple symptoms including hallucinations, lack of behavioral inhibition and cognitive problems, such as decision-making. Past studies found that PCP abusers eventually develop some of the same symptoms present in patients diagnosed with schizophrenia.

Building upon the connection between PCP and schizophrenia, Dr. Roth and his team focused on the symptom that is the most difficult to treat-cognitive deficits subserved by a part of the brain called the prefrontal cortex. Team members include J. David Jentsch, a graduate student in neurobiology; D. Eugene Redmond Jr., M.D., professor of psychiatry and neurosurgery; John D. Elsworth, Ph.D., senior research scientist in psychiatry and pharmacology; Jane R. Taylor, Ph.D., research scientist in psychiatry; Kenneth D. Youngren, a graduate student in neuroscience; and Dr. Roth

Dr. Taylor, a co-author, notes, "These results are exciting because they mimic cognitive deficits associated with schizophrenia and provide a reversible model of the disorder."

Dr. Redmond, co-author and director of the St. Kitts Biomedical Research Foundation, states, "These studies were possible because of the primate facilities, study techniques and support we have developed at the Axion/St. Kitts Biomedical Research Foundation facilities in St. Kitts, West Indies." Graduate student Jentsch, the report's first author, notes, "Up until now, researchers have used only acute doses of PCP in their studies of behavioral effects brought on by PCP injections into laboratory animals. We used chronic or repeated doses of PCP to more closely parallel the same symptoms of schizophrenia that a PCP abuser develops.

"We showed that cognitive deficits are associated with an alteration of a neurotransmitter called dopamine that is already known to be related to schizophrenia," adds Jentsch.

Working from the St. Kitts facility, the Yale research team repeatedly injected primates with PCP. The primates were then evaluated doing an object retrieval task developed by Dr. Taylor. This task tests the cognitive functions of the prefrontal cortex. The team found that primates treated with PCP were significantly less successful at retrieving bananas from a transparent box than saline-treated primates, indicating poor response inhibition.

The team looked for chemical changes in PCP-treated primates by measuring the amounts of dopamine in their brains. "We saw a reduction of dopamine in the dorsolateral prefrontal cortex, the brain area responsible for working memory, and the prelimbic cortex, a brain section thought to control behavioral inhibition," says Jentsch. "There is a strong link between the degree of inhibition of dopamine and in the degree of cognitive dysfunction."

When the primates treated with PCP were given the drug clozapine, they showed a marked improvement in the object retrieval task. The results are similar to the effects of clozapine that have been observed in schizophrenic individuals.

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Yale University School of Medicine

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