Daily nicotine normalizes genetically-induced impairments in brain activity associated with schizophrenia, suggests new research. The finding helps clarify what causes the disease and why those who have it tend to smoke heavily.

The work could ultimately lead to new non-addictive, nicotine-based treatments for some of the 51 million people worldwide who suffer from the disease, the authors of the study envision.

Jerry Stitzel, a researcher at the University of Colorado Boulder Institute for Behavioral Genetics (IBG) and one of four CU Boulder researchers involved in the study, said:

“Our study provides compelling biological evidence that a specific genetic variant contributes to risk for schizophrenia, defines the mechanism responsible for the effect and validates that nicotine improves that deficit."

Surprising Nicotine Effect

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.

“Basically the nicotine is compensating for a genetically determined impairment,” says Stitzel. “No one has ever shown that before."

Led by Uwe Maskos, a researcher at the Institut Pasteur in Paris, 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.

CHRNA5 And Smoking

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?

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.

They did.

Then Stitzel and co-author Charles Hoeffer, also of CU Boulder’s IBG, 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.

They were.

The results validated that the gene variant likely plays a role in schizophrenia by causing hypofrontality, says Stitzel.


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, such as attention deficit hyperactivity disorder and bipolar disorder, the research could ultimately have broad applications for drug development in the mental health field, the authors say.

“This defines a completely novel strategy for medication development,"

says lead author Maskos. Early stage research is already under way to develop drugs that act on nicotinic receptors.

Another potential application of the research:

“Identifying behavioral deficits associated with this mutation can be used for diagnostic or predictive work in schizophrenia,” says Hoeffer.

The work was funded by the Fondation de la Recherche Médical, the Agence Nationale de la Recherche, the Laboratoire d’Excellence BIO-PSY, the European Commission FP7 RTD Project HEALTH-2009-Neurocyp.08-202088 Grant 242167, French National Cancer Institute, and the National Institute of Health.

Fani Koukouli, Marie Rooy, Dimitrios Tziotis, Kurt A Sailor, Heidi C O’Neill, Josien Levenga, Mirko Witte, Michael Nilges, Jean-Pierre Changeux, Charles A Hoeffer, Jerry A Stitzel, Boris S Gutkin, David A DiGregorio & Uwe Maskos Nicotine reverses hypofrontality in animal models of addiction and schizophrenia Nature Medicine (2017) doi:10.1038/nm.4274

Image: Shannon Holman/Flickr

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