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Of Mice and Meth

Amid growing public-health concerns, University of Chicago researchers are working to provide more concrete information on how pregnant mothers' use of the drug methamphetamine may affect their newborns.

Neurobiologist Alfred Heller, PhD'56, MD'60, professor in pharmacological & physiological sciences, and Lisa A. Won, AB'79, PhD'87, research associate in pharmacological & physiological sciences, are entering the second year of a five-year grant from the National Institute on Drug Abuse to study the consequences of maternal use of this harmful drug.

Methamphetamine-dubbed "meth," "crank," or "ice" depending on its form-can be easily made from a mix of over-the-counter cold medicines and common industrial chemicals. Its euphoric rush, with cocaine-like addictive properties, stimulates the central nervous system for up to 24 hours. Though prenatal drug exposure is already known to result in developmental problems, a University of Colorado study found that pregnant meth users comprise one of the most uninformed groups of drug users.

Under the NIDA grant, Heller is using a unique tissue-culture system to study the effects of meth on minute clusters of fetal mouse neurons. Pioneered by U of C faculty members Aron A. Moscona and the late Beatrice Garber, SM'48, PhD'51, these three-dimensional neuron clusters, called aggregates, establish the connections, neurochemistry, and electrophysiology of normal neurons found in the developing brain.

Because the aggregates can live for up to a year, Heller and his team can monitor drug-induced effects during the entire developmental history of neurons, from the fetal to the adult stage.

"This approach gives us a tremendous amount of power to pinpoint where we should go look in the intact animal," Heller explains. "This is a way to look at the cells that we know are susceptible to meth-the dopamine cells-and monitor them for various kinds of defects and sensitivities."

Preliminary results from fetal-cell cultures have already begun to explain the problems that may be faced by meth-affected babies.

Won and Heller treated the cultures with the drug for varying periods of time and then let them grow. The meth-treated cultures' levels of dopamine and serotonin fell dramatically. When methamphetamine was removed from the cultures, the cells resumed normal development, but the cells never attained a normal level of those neurotransmitters.

This concerns researchers because an initial deficit in dopamine-known to be essential to the development of locomotor function-could result in hyperactivity and hypersensitivity. Some children born to mothers who have abused meth, Heller notes, have shown this type of behavior.

"It's like a time out," Heller says. "The critical period is early in development-if you don't have dopamine in this period of time, you can get a hyperactive animal."

Having shown in the first phase of its NIDA grant work that a significant amount of meth does cross from a mother's placenta to her fetus, the team plans to collaborate with U of C pharmacologist Lewis Seiden, AB'56, SM'58, PhD'62, to investigate the behavioral consequences of fetal exposure to meth.

After exposing pregnant mice to the drug, the team will examine the neurologic, cognitive, and behavioral status of the animals to assess the neurotoxic risk of fetal exposure to methamphetamine.

"We and others believe this is far from a trivial issue," Heller cautions, "and may in fact be a major hidden public-health problem."-M.D.B.

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