Can Cause Cell Death

Brief exposure to small amounts of alcohol or anesthetic drugs can trigger nerve cell death in the developing brain, according to research from the American Association for the Advancement of Science (AAAS).
Brief exposure to small amounts of alcohol or anesthetic drugs can trigger nerve cell death in the developing brain, according to research from the American Association for the Advancement of Science (AAAS).
"Our animal studies indicate that significant nerve cell death occurs in the infant mouse brain following exposure to blood alcohol levels equivalent to those a human fetus would be exposed to by maternal ingestion of two cocktails," says investigator John W. Olney, M., the John P. Feighner Professor of Neuropsychopharmacology at Washington University School of Medicine in St. Louis. "With anesthetic drugs, a dose required to lightly anesthetize an infant mouse for about one hour is sufficient to trigger nerve cell death."

For several years, Olney's research has suggested that exposure to alcohol and anesthetic drugs can cause developing brain cells to undergo neuroapoptosis -- brain cell suicide -- but in those previous studies, he was observing damage when laboratory animals were exposed to large amounts of the drugs.

Alcohol's effects
In the most recent studies, alcohol was administered on a one-time basis to infant mice in doses required to produce various blood alcohol levels. When the animals' brains were examined six hours later, the researchers found that blood alcohol elevation in the range of 0.07 percent, lasting for one hour, was sufficient to cause more nerve cell death than in mice not receiving alcohol. The minimum legal blood alcohol concentration for driving in most states is between 0.08 and 0.10 percent.

"Assessing the significance of these findings is complicated by the fact that brain cell suicide occurs naturally at a low rate during development," Olney says. "Transient exposure to small amounts of alcohol or an anesthetic drug causes a two- to four-fold increase in the rate of brain cell suicide. Although more nerve cells die than would have died naturally during that developmental interval, we cannot be certain that those cells would not have died at some later time."

On the other hand, Olney points out it is clear that large doses of alcohol can trigger such extensive death of nerve cells that it causes a permanent reduction in the size of the brain and long-term cognitive impairment. Olney and colleague David F. Wozniak, PhD, research associate professor of psychiatry at Washington University, have demonstrated these permanent deficits in mice and rats, and they believe the same type of pathological process can explain the harmful effects of alcohol on the developing human brain, a condition known as fetal alcohol syndrome.

"It's the best explanation that has been developed so far for the well-known, devastating effects of alcohol on the human fetal brain," Olney says.

Although translating effects from rats and mice to humans is difficult, Olney believes it is unlikely that a single glass of wine would cause substantial damage.

"A single glass is not a problem, but if one glass leads to another and then another on the same day, that is a different matter," Olney says. "Because then blood alcohol levels remain above the toxic threshold for too long, and nerve cells commit mass suicide."

Avoiding alcohol completely
He believes the most prudent advice is to completely avoid alcoholic drinks during pregnancy because, he says, it is not clear how rats, mice and humans compare in sensitivity to alcohol.

Olney's research has demonstrated that rat and mouse brains are sensitive to this toxic effect during a development stage known as the brain growth spurt. Called synaptogenesis because it is the time when brain cells form most of their synaptic interconnections, the brain growth spurt in humans lasts from about the sixth month of pregnancy to a child's third birthday. In rats and mice, synaptogenesis occurs during the first few weeks after the animal is born.

Nerve cells are genetically programmed to commit suicide if they fail to make synaptic connections on time. Alcohol and anesthetic drugs interfere with the brain's neurotransmitter systems and with the formation of those synaptic connections, automatically activating a signal within the neuron that directs it to commit suicide.

Olney believes the phenomenon his team is studying can be viewed as a "final common pathway" type of mechanism that might explain a wide range of developmental neuropsychiatric problems.

Because different networks in the brain are organized at different times during synaptogenesis, different populations of cells will commit suicide in response to exposure to alcohol or anesthetic drugs depending on the timing of that exposure. Thus, exposure at one developmental stage may produce one type of disturbance while exposure at another period of development could produce a very different effect.

Psychiatric illnesses
Consistent with that concept, Columbia University psychiatrist Ezra Susser, MD, and his colleagues reported new findings, soon to be published in the journal Environmental Health Perspectives, suggesting that young adults diagnosed with schizophrenia were significantly more likely to have been exposed to lead in the womb. Susser believes lead exposure also might cause damage through the cell suicide mechanism, with schizophrenia being the long-term consequence.

"The results of our study suggest that lead-induced prenatal damage to the developing brain may show itself decades following initial exposure to the substance," Susser says.

The idea that damage from exposure to substances such as alcohol, anesthetics and lead can contribute to a wide range of psychiatric illnesses also is supported by work from Ann P. Streissguth, MD, of the University of Washington School of Medicine in Seattle. She has followed the impact of maternal alcohol use on the children of women who were pregnant in 1974, looking at the secondary disabilities encountered by people with fetal alcohol syndrome and fetal alcohol effects.

She found that 90 percent of those exposed to excessive alcohol in the womb reported mental health problems.

"Many had attention deficit problems," Streissguth says. "But there also were high rates of psychosis and suicide attempts and almost half suffered from major depression."

More basic work from Charles F. Zorumski, MD, the Samuel B. Guze Professor and head of the Department of Psychiatry at Washington University School of Medicine in St. Louis, might help explain why.

"Previous studies in patients with fetal alcohol syndrome suggest that they have increased risk of major psychiatric disorders," Zorumski says. "In our work with laboratory rats exposed to alcohol and anesthetic drugs during synaptogenesis, we have observed that they catch up and seem to develop normally, but during adolescence they develop problems."

Zorumski has found that animals exposed to alcohol and anesthetic drugs have difficulty performing maze tests that are used help to measure spatial learning and spatial working memory in rats. Their brains also exhibit defects in neuronal processes that occur in the hippocampus, a brain structure known to be important in learning and memory.

Zorumski's team ran electrical currents through neuronal slices taken from the hippocampus to induce a process known as long-term potentiation (LTP), which enhances communication between neurons by promoting the movement of the chemical messenger glutamate between brain cells. In normal rats, the stimulus Zorumski used usually produces a lasting 40 to 50 percent enhancement of glutamate transmission. But rats exposed to alcohol and anesthetics had decreases in LTP ranging from 75 to 100 percent.

In other words, some of the exposed animals had a complete loss of LTP. His team also tested a related process called long-term depression (LTD). When treated with an LTD stimulus, normal slices of the rat hippocampus experience a 30 to 40 percent decrease in synaptic transmission. But those rats treated with alcohol or anesthetics experienced a complete elimination of LTD. What LTD does is not well understood, but there is evidence suggesting it is important in spatial working memory and adaptation to new environments.

The rats appeared to behave normally in most other ways, and there were no outward signs of brain damage.

"If similar brain damage had occurred in a human infant, it appears there would not be any overt signs that would alert you to it," Zorumski says. This area of research has repeatedly identified a relationship between certain classes of drugs that inhibit nerve cell activity and damage to the developing brain. Anesthetic drugs tend to work in one of two ways, both of which inhibit nerve cell activity: Either they inhibit excitatory neurotransmission in the brain, or they enhance inhibitory neurotransmission.

Anesthetic drugs
The excitatory system that stimulates nerve cells is what scientists call the NMDA glutamate transmitter system. In 1998, Olney and colleague Vesna Jevtovic-Todorovic, MD, PhD, associate professor of anesthesiology at the University of Virginia, discovered that the drug nitrous oxide (laughing gas) works by inhibiting the NMDA glutamate system. Another anesthetic drug known as Ketamine also works by inhibiting the NMDA glutamate system. Other anesthetic drugs work by enhancing the inhibitory activity of GABA (Gamma Amino Butyric Acid), which is the primary inhibitory transmitter in the brain.

Olney and his colleagues have demonstrated that when the developing brain is exposed to drugs that block NMDA glutamate activity, nerve cells in the brain commit suicide. They also found that drugs that enhance GABA activity can cause nerve cells in the developing brain to self-destruct.

Those findings prompted them to study alcohol, which is known both to block NMDA glutamate activity and also to enhance GABA activity. They found that alcohol powerfully triggers nerve cell suicide in the developing brain, providing a likely explanation for the learning and memory disturbances associated with the human fetal alcohol syndrome.

"In all of these studies, we have found that drugs that enhance GABA inhibition or that inhibit glutamate excitation can trigger massive cell suicide in the developing brain," Olney says.

Olney believes by better understanding the mechanism through which alcohol and drugs cause brain cell suicide, it might be possible to prevent it. He compares the process to a line-up of dominoes in which one step triggers the next, but by understanding that cascade, he hopes it might be possible to intervene.

"We're going to see if there are some steps in that line-up of dominoes that we can interfere with to prevent the suicide signal from being activated," he

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