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CU/VA Researchers Identify Schizophrenia Gene as Nicotine Receptor
A team of researchers, led by a University of Colorado Health Sciences Center/Denver Veteran's Affairs Medical Center professor, has pinpointed a gene that carries significant risk for schizophrenia, a devastating mental illness that affects some 4 million Americans. The new findings also may explain why 80 percent of schizophrenics are heavy smokers.
The research findings are described in the Jan. 21 issue of the Proceedings of the National Academy of Sciences.
A basic physiological defect associated with people with schizophrenia is an inability to ignore irrelevant sensory information, or "background noise" in their surroundings, said Robert Freedman, MD, lead investigator on the study. Dr. Freedman is a professor of psychiatry and pharmacology at the CU-Health Sciences Center and director of the VA's Schizophrenia Research Center.
The inheritance of this filtering defect, in which the brain's ability to decrease its sensitivity to repeated stimuli is affected, was traced in nine families in Colorado and Utah, each of which had multiple cases of schizophrenia. The deficit was genetically linked to a nicotinic cholinergic receptor on chromosome 15, the alpha-7 nicotinic receptor, which has a critical role in the mechanism responsible for sensory filtering in the brain.
The alpha-7 nicotinic receptor gene can be activated by a neurotransmitter called acetylcholine, and also by nicotine from tobacco.
"This gene, which is a receptor for nicotine, also turns out to carry a major risk for schizophrenia, an illness that is characterized by extremely heavy smoking," Dr. Freedman said. "While smoking tobacco is not an effective treatment for schizophrenia, people who suffer from the illness may be smoking in an unconscious effort to stimulate the receptor and find some relief."
When the receptor is stimulated, the person is able to become more focused, and more able to filter out repeated sounds or background noise, Dr. Freedman added.
About 80 percent of schizophrenics smoke, many of them more than two packs a day. This is the first example of heavy smoking in a particular group in the population that has a genetic defect related to a brain receptor that is activated by nicotine.
Although the effects of nicotine are extremely brief, the nicotine works to normalize the patients' sensory processing, Dr. Freedman said. Smoking is not an effective treatment; trying to repeat the effect by smoking causes a loss of sensitivity of the nicotinic receptor, causing it to lose receptivity. Nicotine from other sources, such as nicotine patches or chewing gum, do not provide enough nicotine to produce positive effects.
Other genes may play a role in the risk for schizophrenia, but evidence now shows the alpha-7 nicotinic receptor may be the most powerful. Still, most people with the defective receptor may have a filtering problem, but they will not get schizophrenia in the absence of other factors, Dr. Freedman said.
"We now have both biological and genetic evidence that this gene plays a critical role in schizophrenia," Dr. Freedman said. "Further research could lead to more effective diagnosis and treatment, including drug therapy and gene therapy to treat this devastating mental illness."
Co-authors on the published study included 11 researchers at the CU-Health Sciences Center, the Denver Veteran's Affairs Medical Center and Eleanor Roosevelt Institute for Cancer Research, as well as researchers at the University of Utah School of Medicine, Salt Lake City; Baylor College of Medicine, Houston, Whitehead Institute for Biomedical Research, Cambridge, Mass., and the National Institutes of Health.
The University of Colorado Health Sciences Center is one of four campuses in the University of Colorado system. Located in Denver, Colo., the campus includes schools of medicine, nursing, pharmacy, dentistry, graduate school and two hospitals.
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