Apnea of prematurity occurs in up to 85 percent of all prematurely born human infants, and obstructive sleep apnea occurs in 3 to 27 percent of all children. Data from previous studies suggests that diminished release of brain dopamine may be responsible for behaviors such as impulsiveness and distractibility, reduced self control, and impaired learning, which are hallmark traits associated with ADHD. Previous studies in Dr. Decker's laboratory at Emory have shown that newborn rats who experience repetitive drops in blood oxygen levels go on to develop behavioral traits similar to those seen in humans with ADHD. This is the first time, however, that researchers have linked repetitive reductions in blood oxygen levels during a period of critical brain development to long-lasting deficiencies in release of dopamine specifically within the striatum, which is one of the brain regions important in modulating behavior, learning and memory.
The scientists exposed newborn rats from 7 to 11 days old to either 20-second bursts of a gas containing low oxygen content or to bursts of compressed air. Once the rats matured into juveniles, the scientists studied their locomotive activity and brain dopamine levels. They found that juvenile rats exposed to brief reductions in oxygen during their neonatal period had a 50 percent reduction in release of dopamine and were hyperactive.
Traditionally, ADHD has been attributed to genetic causes, environmental toxins or maternal use of nicotine, alcohol or drugs. Also, researchers generally have believed that the newborn brain is somewhat resistant to subtle disturbances in blood oxygenation. This study demonstrates in rats, however, that while long-term decreases in the release of dopamine can occur following as few as five days of subtle, repetitive reductions in blood oxygen levels during a critical window of brain development, the hyperactivity and impaired learning that also occur are not noticeable until later, when juvenile animals are old enough to display these behaviors.
The Emory scientists found that juvenile rats exposed to repetitive drops in blood oxygen levels as newborns also had a 50 percent increase in the level of dopamine stored in the brain tissue of the striatum compared to control rats and a reduction in the release of dopamine, showing that instead of releasing dopamine, they were abnormally storing it.
"By linking reductions in blood oxygen during critical times of development to changes in dopamine function, we hope to shed light on the mechanisms of ADHD, which have been poorly understood to this point," said Dr. Keating. "Our results show that a relatively common occurrence in newborns could have long-lasting negative effects, and we believe our model has great potential for creating new insights and leading to new interventions and therapies."
"Our research also could help explain why amphetamines, such as Ritalin, and other non-amphetamines, such as Wellbutrin, that increase levels of brain dopamine are an effective treatment for children with ADHD," Dr. Decker said. "So far scientists haven't sorted out which neurotransmitters are responsible for this effect, but if that could be narrowed down to just dopamine, as suggested by our data, it would provide a basis for developing drugs without the potential addictive properties of existing therapies."
The Emory investigators are exploring different ways to measure altered behavioral outcomes in rats to further confirm the similarity of these behaviors to those identified in ADHD. They also are planning studies aimed at preserving the brain dopamine system in individuals at risk for repetitive reductions in blood oxygenation. These studies could include non-invasive, subtle dietary changes in the mother and the newborn.
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