Mother's drug use increases risks for male offspring

July 13, 2001

Exposure before birth to methamphetamine, an increasingly popular "club" drug, renders males, even as adults, much more susceptible to the drug's brain-damaging effects, reveals a study performed in mice by researchers at the University of Chicago.

If males who were prenatally exposed to methamphetamine take the drug themselves as teens or adults, the increased toxicity could hasten the onset of brain disorders such as Parkinson's disease, warn the authors in the August issue of the Journal of Pharmacology and Experimental Therapeutics, published electronically on July 13, 2001.

"No one who values his or her brain should take this drug," cautions neurotoxicologist Alfred Heller , MD, PhD, professor of neurobiology, pharmacology and physiology at the University of Chicago and director of the study. "If you're male, and if your mother took methamphetamine -- and it's difficult to be certain she didn't -- you should not go near this drug."

Methamphetamine -- also known as "meth" or "chalk," or when smoked as "crystal," "crank" or "ice" -- is the world's second most widely used illicit drug, according to the World Health Organization, and is rapidly gaining popularity. After claiming a foothold in the Southwest in the early 1990s, it has spread across much of the United States.

"We now are seeing high levels of methamphetamine abuse in many areas of the Midwest," notes an alert on the National Institute on Drug Abuse Web site, "in both urban and rural settings, and by very diverse segments of the population."

Cheap, long-lasting, easy to make, easy to take and perceived as relatively safe, this stimulant is widely used by young women because it elevates mood, boosts energy, suppresses appetite and helps with weight loss.

Researchers have long known that methamphetamine has multiple side effects. It damages neurons that use the neurotransmitter dopamine to relay signals. Women who abuse the drug during pregnancy have increased risk of premature delivery. Their newborns are often unusually irritable. But because the drug has only recently become so popular, there is limited information about its long-term effects on users' offspring.

Last spring, recognition of methamphetamine's blossoming popularity among young women, and the uncertainty about its effects on an exposed fetus, provoked NIDA to call for research on how the drug affects brain development for those exposed in utero.

Heller's group at the University of Chicago had already developed a mouse model of prenatal methamphetamine exposure. They determined the dose that exposed the mouse fetal brain to similar concentrations of methamphetamine as in human infants and then studied its effects on the exposed mice and their offspring.

The key finding was that male mice who were exposed to the drug before birth and then exposed again as adults (at 11 weeks old), were significantly more vulnerable to methamphetamine's neurotoxic effects. These males suffered damage to the dopamine-using neurons, particularly in areas of the brain known as the substantia nigra and the striatum, the system that is damaged in Parkinson's disease.

Why the effect was so much greater in males than females is unclear. It may be connected with the rise in body temperature associated with use of the drug. The amount of brain damage was closely associated with this increase in body temperature in exposed mice. Methamphetamine increases core temperatures more in males than in females.

The researchers also suggest that a likely mechanism for the increase in brain damage is that fetal exposure to methamphetamine increases the release of dopamine from adult brain cells by methamphetamine.

When stimulated later in life by this drug, these preconditioned nerve cells release abnormal amounts of dopamine, which accumulates outside the cells, where it can be chemically altered or oxidized. Heat exacerbates this dopamine secretion. When the altered neurotransmitters are taken back up into these nerve cells, they can be toxic. In fact, drugs that block re-uptake can prevent this toxicity.

The enhanced neurotoxicity in response to methamphetamine in male animals exposed in utero "may be an additional risk factor in the development of parkinsonism," note the authors. "With age, the persistent damage to the dopaminergic system may predispose these individuals to brain disorders."

Although Parkinson's disease doesn't immediately appear in these animals, or in most human drug users, the drug may be setting the stage for early disease onset. People begin to exhibit symptoms, such as slowed movements, rigidity, and tremors, only after losing more than 80 percent of the dopamine-producing cells in the substantia nigra.

"Regular methamphetamine users, or those at increased risk because of prenatal exposure, may have a head start on this process," suggests Heller.

Additional authors of the study include Nancy Bubula, Robert Lew and Lisa Won of the University of Chicago, and statistician Barbara Heller, from the Illinois Institute of Technology. The research was supported by NIDA grant DA09764.

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