Scientists at the School of Medicine are a step closer to understanding the causes of, and possible treatments for, cognitive dysfunctions that are associated with schizophrenia. The research supports the increasingly popular scientific view that dopamine plays a more complex role in the biology of schizophrenia than previously thought.
Robert H. Roth, professor of psychiatry and pharmacology, led a neuroscience research team that studied the behavior of African green monkeys that were given repeated doses of phencyclidine (PCP), a drug that is often abused by humans. Past studies had shown that PCP abusers eventually develop some of the same symptoms present in patients diagnosed with schizophrenia, a brain disorder with multiple symptoms including hallucinations, lack of behavioral inhibition and problem with cognitive abilities, such as decision making.
To explore the connection between PCP and schizophrenia, the researchers gave repeated doses of the drug to primates at the Axion/St. Kitts Biomedical Research Foundation in St. Kitts, West Indies. The scientists then observed the primates as the animals attempted to retrieve bananas from a transparent box -- a task designed to test the cognitive functions of the prefrontal cortex.
"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," notes J. David Jentsch, a graduate student in neurobiology who is the report's first author. "We used chronic or repeated doses of PCP to more closely parallel the same symptoms of schizophrenia that a PCP abuser develops."
The team found that the primates receiving PCP were significantly less successful at the retrieval task than those that were given saline injections -- indicating poor response inhibition, according to Mr. Jentsch.
The researchers then looked for chemical changes in the PCP-treated primates by measuring the amounts of dopamine in their brains. They found reduced levels of dopamine in the areas of the brain responsible for working memory and for behavioral inhibition, explains Mr. Jentsch. "We showed that cognitive deficits are associated with an alteration of a neurotransmitter called dopamine that is already known to be related to schizophrenia. 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 called clozapine, which is used to treat schizophrenia, 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.
According to Professor Roth, "The results of this study open up countless possibilities for future treatment strategies. It could lead to better drugs for cognitive brain dysfunction and poor response inhibition, which are common symptoms of schizophrenia." These symptoms are also the most difficult to treat, he adds.
Jane R. Taylor, research scientist in psychiatry and another member of the investigative team, notes, "These results are exciting because they mimic cognitive deficits associated with schizophrenia and provide a reversible model of the disorder."
The research team published its findings in the Aug. 15 issue of the journal Science. The other team members were Dr. D. Eugene Redmond Jr., professor of psychiatry and surgery (neurosurgery) and director of the St. Kitts Biomedical Research Foundation; John D. Elsworth, senior research scientist in psychiatry; and Kenneth D. Youngren, a graduate student in neuroscience.