(Great Neck, NY - November 27, 2008) — The most treatment-resistant symptoms of schizophrenia are cognitive impairments. Now, researchers from Ohio State University and the University of Maryland School of Medicine report they have traced the effects of elevated levels in the brain of the compound kynurenic acid to problem-solving deficits in schizophrenia.

The finding, announced Nov. 18th at the Society for Neuroscience meeting in Washington, D.C., suggests that drugs used to suppress kynurenic acid might be an important supplement to current schizophrenia medications, which treat the hallucinations and delusions of the disorder but not the cognitive problems.

Among the participants in the research, NARSAD 2002 Distinguished Investigator Robert Schwarcz, professor and director of neuroscience research in the University of Maryland’s department of psychiatry, is a leading expert in the study of kynurenic acid. John P. Bruno, professor of psychology, psychiatry and neuroscience at Ohio State University was the principal investigator.

The researchers tested kynurenic acid’s effects on cognitive abilities in experimental animals. Seven rats were given a compound that stimulated excess production of the molecule in their brains. These rats and a comparable number of control animals were then subjected to a test gauging their ability to make what is called an extra-dimensional set shift, requiring them to change response strategies based on changing contingencies, in this case a quest for food.

Only 28 percent of the rats with elevated kynurenic acid were able to solve problems to receive a food reward compared to 100 percent of the controls. Before the intervention, all of the animals were equally able to find the food under changing circumstances.

Kynurenic acid essentially exacerbates a phenomenon already observed in patients with schizophrenia: two neurotransmitters in their brains, acetylcholine and glutamate, critical to cognition, are not as active as they need to be to allow for normal problem-solving capabilities.

The activity of acetylcholine and glutamate is partially regulated by proteins called alpha-7 receptors. In schizophrenia, the neurotransmitters are already at abnormally low levels, most likely because of genetic mutations. Excess kynurenic acid, which inhibits alpha-7 receptor activity, suppresses release of the neurotransmitters even further. The researchers were able to precisely gauge the effects through the use of microelectrodes painlessly inserted in the animals’ brains to measure neurotransmitter levels before and after introduction of the agent that elevates kyurenic acid. The real-time measurements allow the scientists to prove the causal relationship between the elevated compound and the reduced presence of the neurotransmitters. 

Antipsychotic agents used to control hallucinations and delusions act on different neurotransmitters. This research raises the hope that agents targeting kynurenic acid production could be part of a medication cocktail that could help restore neurochemistry responsible for cognition.

_{(This news article was adapted with permission from Ohio State University.)}