July 13, 2015
A Dartmouth study suggests that increased levels of a particular brain molecule during adolescence may permanently impair cognition and increase susceptibility to drug abuse later in life.
The concentration of the molecule kynurenic acid (KYNA) is known to be elevated in the brains of people with schizophrenia, and the new findings suggest that targeting KYNA with medications may help to reduce schizophrenia’s symptoms and the odds of drug addiction.
The findings are the first to show the consequence of elevated KYNA concentrations during neurodevelopment and provide insight into cognitive and behavioral impairments that result from exposure to KYNA during adolescence.
The study appears in the journal Frontiers in Behavioral Neuroscience. A PDF is available on request.
Schizophrenia, which affects about 1 percent of Americans, is a chronic and severe brain disorder in which people interpret reality abnormally and also have impairments in attention and memory. Its causes aren’t known, but scientists think several factors are involved, including abnormalities in brain chemistry and structure as well as environmental factors. Schizophrenia usually starts during late adolescence or early adulthood and is triggered by stressors combined with biological predisposition, such as genetic mutations that result in high KYNA levels.
Changes in brain-reward systems are thought to contribute significantly not only to the cognitive and behavioral impairments of schizophrenia but also to co-occurring substance abuse. Such abuse results from the brain’s over-responsiveness to drug-related stimuli and reward-related cues. Presently, there are few treatments for a dual diagnosis and little is known about the neurochemical reactions that underlie the problem.
The KYNA molecule, which is in all of our central nervous systems, is critically involved in brain development, flexibility and behavior, but its levels are significantly increased in the brains of people with schizophrenia. The Dartmouth researchers previously found that experimental increases in KYNA concentrations in adult rats led to cognitive impairments that also are exhibited by schizophrenic people, and that are unresponsive to current treatments.
One goal of the new study was to determine whether changes in KYNA affect animals’ reward-related behavior. The researchers also increased KYNA levels in young rats because the brain is still developing during adolescence. They then looked at the effects in adulthood, after KYNA levels were back down, to see what long-lasting effects there may be.
The study’s results showed that high levels of KYNA during the rats’ adolescence led to an increase in addictive behavior later in adulthood. Elevated KYNA also produced a seemingly permanent change in their brain function as evidenced by an inability of cells in the hippocampus (learning, memory, reward areas) to undergo plasticity. In other words, that part of the brain was no longer flexible and could not exhibit changes in activity based on experience like normal brains.
“Our findings bring awareness to the involvement of KYNA in mental illness -- specifically schizophrenia but potentially others -- and it also provides a new therapeutic inroad. Indeed, other labs are currently working on drugs that reduce KYNA levels,” says senior author David Bucci, a professor of Psychological and Brain Sciences.
Professor David Bucci is available to comment at David.J.Bucci@dartmouth.edu.
The research was supported by the National Institutes of Health.