A steady stream of nicotine normalizes genetically-induced impairments in brain activity associated with schizophrenia, according to new research involving the University of Colorado Boulder. The finding sheds light on what causes the disease and why those who have it tend to smoke heavily. Researchers envision their work could lead to new non-addictive, nicotine-based treatments for some of the 51 million people worldwide who suffer from the disease. The study found that when mice with schizophrenic characteristics were given nicotine daily, their sluggish brain activity increased within two days. Within one week it had normalized. The international team of scientists set out to explore the underlying causes of 'hypofrontality' (a reduction of neuronal firing in the prefrontal cortex of the brain). Hypofrontality is believed to be the root cause of many of the signature cognitive problems experienced by schizophrenics, including trouble paying attention, remembering things, making decisions and understanding verbal explanations. Previous genome-wide association studies have suggested that people with a variation in a gene called CHRNA5 are more likely to have schizophrenia, but the mechanism for that association has remained unclear. People with that variant are also more likely to smoke.
Eighty to 90 percent of people with schizophrenia smoke and most are very heavy smokers, a fact that has long led researchers to suspect they are self-medicating. For the study, the researchers set out to answer several questions: Does a variant in the CHRNA5 gene lead to hypofrontality. If so, how? And does nicotine somehow interrupt this effect? Eighty to 90 percent of people with schizophrenia smoke and most are very heavy smokers, a fact that has long led researchers to suspect they are self-medicating. To do so, the research team first took mice with the CHRNA5 gene variant and used state-of-the-art brain imaging technologies to see if they had hypofrontality. Then researchers, conducted behavioral tests to see if the mice shared key characteristics of schizophrenics, like being unable to suppress a startle response and being averse to social interaction. The results validated that the gene variant likely plays a role in schizophrenia by causing hypofrontality. Nicotine appeared to reverse this in the mice, normalizing brain activity by acting on nicotinic receptors in regions of the brain key to healthy cognitive function. Because hypofrontality is also associated with addiction and other psychiatric conditions, the research could ultimately have broad applications for drug development in the mental health field.