Gender-dependent enhanced adult neurotoxic response to methamphetamine following fetal exposure to the drug

Methamphetamine use by females of child-bearing age has become a major publ ic health concern in terms of the long-term risk to the exposed fetus. We e xamined the possibility of enhanced adult neurotoxic potential of the drug in offspring that had been exposed to methamphetamine in utero during gesta tional 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 pr imarily 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 met hamphetamine-treated males compared with saline-treated animals. Some effec ts of prenatal methamphetamine exposure were observed in female offspring, but these were limited to striatal levels of 3-MT and HVA. Differential gen der sensitivity to the neurotoxic effect of methamphetamine was shown to be correlated with hyperthermic response. Hyperthermic effects, however, do n ot account for the increased susceptibility of prenatal methamphetamine-tre ated males to drug-induced striatal DA neurotoxicity since methamphetamine challenge did not evoke a significantly greater hyperthermic response in th ese animals compared with prenatal saline-treated males. The findings raise the concern that male methamphetamine abusers may be at risk for an enhanc ed neurotoxic risk if they were exposed to the drug in utero.