Vol. 298, Issue 2, 769-779, August 2001

Gender-Dependent Enhanced Adult Neurotoxic Response to Methamphetamine following Fetal Exposure to the Drug

Alfred Heller, Nancy Bubula, Robert Lew, Barbara Heller and Lisa Won

Department of Neurobiology, Pharmacology, and Physiology, The University of Chicago, Chicago, Illinois (A.H., N.B., R.L., L.W.); and Department of Applied Mathematics, Illinois Institute of Technology, Chicago, Illinois (B.H.)

Methamphetamine use by females of child-bearing age has become a major public health concern in terms of the long-term risk to the exposed fetus. We examined the possibility of enhanced adult neurotoxic potential of the drug in offspring that had been exposed to methamphetamine in utero during gestational days 7 to 18. While basal levels of monoamines were not affected by prenatal exposure to methamphetamine, we observed an enhanced neurotoxicity in adult male offspring following drug challenge with effects localized primarily to the dopaminergic nigrostriatal projection. This was evidenced by greater methamphetamine-induced reductions of dopaminergic markers in the striatum [dopamine (DA), dihydroxyphenylacetic acid, homovanillic acid (HVA), and 3-methoxytyramine (3-MT)] and ventral brainstem (DA) of prenatal methamphetamine-treated males compared with saline-treated animals. Some effects of prenatal methamphetamine exposure were observed in female offspring, but these were limited to striatal levels of 3-MT and HVA. Differential gender sensitivity to the neurotoxic effect of methamphetamine was shown to be correlated with hyperthermic response. Hyperthermic effects, however, do not account for the increased susceptibility of prenatal methamphetamine-treated males to drug-induced striatal DA neurotoxicity since methamphetamine challenge did not evoke a significantly greater hyperthermic response in these animals compared with prenatal saline-treated males. The findings raise the concern that male methamphetamine abusers may be at risk for an enhanced neurotoxic risk if they were exposed to the drug in utero.