Summary: Study sheds light on how nicotine affects the brains of those with schizophrenia, and why those with the disease tend to be heavy smokers.
Source: University of Colorado at Boulder.
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.
Ultimately the authors of the study, released online today in the journal Nature Medicine, 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.
“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,” said Jerry Stitzel, a researcher at the Institute for Behavioral Genetics (IBG) and one of four CU Boulder researchers on the study.
Led by Uwe Maskos — a researcher at the Institut Pasteur in Paris, France — 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.”
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?
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.
Other co-authors included IBG research associates Josien Levenga and Heidi O’neill.
Source: Jerry Stitzel – University of Colorado at Boulder
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Nicotine reverses hypofrontality in animal models of addiction and schizophrenia” by 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 in Nature Medicine. Published online January 239 2017 doi:10.1038/nm.4274
Nicotine reverses hypofrontality in animal models of addiction and schizophrenia
The prefrontal cortex (PFC) underlies higher cognitive processes that are modulated by nicotinic acetylcholine receptor (nAChR) activation by cholinergic inputs. PFC spontaneous default activity is altered in neuropsychiatric disorders, including schizophrenia—a disorder that can be accompanied by heavy smoking. Recently, genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) in the human CHRNA5 gene, encoding the α5 nAChR subunit, that increase the risks for both smoking and schizophrenia. Mice with altered nAChR gene function exhibit PFC-dependent behavioral deficits but it is unknown how the corresponding human polymorphisms alter the cellular and circuit mechanisms underlying behavior. Here we show that mice expressing a human α5 SNP exhibit neurocognitive behavioral deficits in social interaction and sensorimotor gating tasks. Two-photon calcium imaging in awake mouse models showed that nicotine can differentially influence PFC pyramidal cell activity by nAChR modulation of layer II/III hierarchical inhibitory circuits. In α5-SNP-expressing and α5-knockout mice, lower activity of vasoactive intestinal polypeptide (VIP) interneurons resulted in an increased somatostatin (SOM) interneuron inhibitory drive over layer II/III pyramidal neurons. The decreased activity observed in α5-SNP-expressing mice resembles the hypofrontality observed in patients with psychiatric disorders, including schizophrenia and addiction. Chronic nicotine administration reversed this hypofrontality, suggesting that administration of nicotine may represent a therapeutic strategy for the treatment of schizophrenia, and a physiological basis for the tendency of patients with schizophrenia to self-medicate by smoking.
“Nicotine reverses hypofrontality in animal models of addiction and schizophrenia” by 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 in Nature Medicine. Published online January 239 2017 doi:10.1038/nm.4274