NIDA-supported study has shown that prenatal exposure to drugs such as phencyclidine (PCP), ketamine, and alcohol causes widespread damage to the developing rat brain. Though conducted with animals, the study raises concerns not only about the effects of abusing these drugs during pregnancy but also about the legitimate use of ketamine and similar anesthetic medications during pregnancy and early childhood, the researchers say.
PCP, ketamine, and alcohol all belong to a class of drugs that prevent brain cells from picking up glutamate, a chemical messenger that cells use to communicate with each other. The new research by Dr. John Olney of Washington University School of Medicine in St. Louis and scientists from Humboldt University in Berlin and University College in London found that when such drugs block developing nerve cells in late fetal and newborn rats from receiving glutamate, they dramatically accelerate a natural process called programmed cell death.
Normally, programmed cell death, or apoptosis, serves a positive function. During development of the central nervous system, this process eliminates brain cells that are not serving any useful purpose. Such cells are abundant when the developing brain is rapidly generating billions of new cells and connecting them with each other. Cells needed only during early stages of development, surplus cells, and faulty cells that fail to complete their proper connections all must be eliminated to ensure efficient brain functioning.
NMDA-receptor blocking drugs, such as PCP, ethanol, and MK801, triggered extensive programmed cell death in the forebrains of 7-day-old rats. These brain images were obtained 24 hours after rats were treated with either MK801 or an inactive saline solution. The dark spots in the brain of the MK801-treated rat show millions of degenerating nerve cells in key brain areas compared to the insignificant amounts of degenerating nerve cells in the brain of the saline-treated rat. (Brain images at X9.8 magnification.)
However, in Dr. Olney's study, the researchers found that a single administration of a drug that blocked glutamate transmission for at least 4 hours when rats' brains were undergoing rapid development triggered a massive wave of programmed cell death, eradicating millions of nerve cells in key areas of the brain.
In the study, the researchers administered a drug called MK801 to pregnant and newborn rats. Like PCP, ketamine, and alcohol, MK801 blocks N-methyl-D-aspartate (NMDA) receptors, sites on nerve cells through which glutamate transmits its signals. The scientists administered the substance to pregnant rats 72, 48, or 24 hours before the rats gave birth and to infant rats on the 1st, 3rd, 7th, 14th, or 21st day of life. Examination of the fetal and infant brains 24 hours after treatment showed MK801-treated rats had very high concentrations of degenerating nerve cells in many brain regions. Rats treated with inactive saline solution on the same days had low concentrations of degenerating cells, consistent with natural program-med cell death.
MK801 triggered the most extensive programmed cell death in the forebrain of rats treated when they were 7 days old, a period when this important brain area is developing rapidly. "Many areas of the brain were particularly hard-hit," says Dr. Olney. For example, the numbers of degenerating neurons in treated rats were 3- to 39-fold higher than the numbers in untreated rats in several areas of the thalamus and cerebral cortex. "These regions of the brain are central to how [animals, including humans,] interact with the environment, integrate sensory information into the brain, and perform cognitive processes," Dr. Olney says.
Because rats are born at an earlier stage of their development than humans, the rapid brain growth that occurs in their first week of life corresponds to the growth spurt in human brains that begins in the last trimester of pregnancy and extends through the first 2 to 3 years of life. This indicates that the period of peak vulnerability of the human forebrain to the nerve damage induced by NMDA-receptor blocking drugs may include the entire third trimester, the researchers conclude. It also indicates a need to re-evaluate the use of NMDA-receptor blocking anesthetic medications, such as ketamine and nitrous oxide, during pregnancy and early childhood. "Additional research is needed to determine if we can establish a margin of safety for using these agents," Dr. Olney says.
To confirm that it was the blockade of NMDA receptors that induced the damaging effects in the developing rat brain, the researchers administered several other NMDA-receptor blocking drugs, including PCP and ketamine, to newborn rats. These drugs all triggered a pattern of cell degeneration similar to that induced by MK801. However, several factors may limit the amount of fetal brain damage that could occur when women abuse these drugs during pregnancy, Dr. Olney notes. For example, ketamine is a relatively short-acting drug, and the study used several doses to ensure sufficient receptor blockade to trigger apoptosis. As for PCP, its ability to induce psychotic effects in humans reduces the likelihood of someone taking multiple doses. "Nevertheless, the duration of blockade of the NMDA receptor that occurs when people abuse these drugs would probably be right at the threshold where prenatal damage could result," he says, "although such damage would probably not be as severe as shown in this study."
"These findings suggest that pregnant women who abuse drugs such as ketamine and PCP are risking considerable harm to the brains of their unborn children during critical stages of their development," says Dr. Jerry Frankenheim of NIDA's Division of Neuroscience and Behavioral Research. If the damage to nerve cells caused by these drugs in rats occurs in the human fetus, it could lead to learning and behavior problems in childhood, he says.
Rats are born at an earlier stage of their development than humans. The rapid brain growth that occurs in their first week of life corresponds to the growth spurt in human brains that begins in the last trimester of pregnancy and continues in the first few years of life. Because NMDA-receptor blocking drugs triggered the most damage to the rats' brains during this period, the researchers at Washington University speculate that the human brain may be most vulnerable to such drugs during the entire third trimester and approximately the first 2 years of life.
The developmental harm that could result from fetal brain damage caused by using NMDA-receptor blocking drugs during pregnancy can be illustrated by the known effects of using alcohol during pregnancy, says Dr. Olney. These effects, which are referred to as fetal alcohol syndrome, can range from attention-deficit hyperactivity disorder and various degrees of learning disabilities to mental retardation.
NMDA-blockade is one of the primary ways that alcohol damages the developing brain, according to a separate study conducted by Dr. Olney and his colleagues. They found that blocking NMDA receptors with alcohol for several hours during periods when the developing brain is most vulnerable produces damage similar to that caused by MK801 and PCP. "The kind of damage to these brain centers that we are finding with drugs such as alcohol, PCP, and ketamine can have far-reaching effects on behavioral and psychiatric well-being," he says.
Ikonomidou, C.; Bosch, F.; Miksa, M.; Bittigau, P.; Vöckler, J.; Dikranian, K.; Tenkova, T.I.; Stefovska, V.; Turski, L.; and Olney, J.W. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283(5398):70-74, 1999. [Abstract]
Ikonomidou, C.; Bittigau, P.; Ishimaru, M.J.; Wozniak, D.F.; Koch, C.; Genz, K.; Price, M.T.; Stefovska, V.; Hörster, F.; Tenkova, T.; Dikranian, K.; and Olney, J.W. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 287(5455): 1056-1060, 2000. [Abstract]