Neonatal Methamphetamine in the Rat: Evidence for Gender-specific Differences upon Tyrosine Hydroxylase Enzyme in the Dopaminergic Nigrostriatal System

Methamphetamine (Meth) neurotoxicity upon the mesencephalic dopaminergic systems was demonstrated in the adult, both in humans and in experimental models. In the rat, the development and maturation of the dopaminergic systems is accomplished during the first month of postnatal life, a period of particular vulnerability to environmental influences. In this study, the effect of Meth exposure during the first month of life was assessed in the nigrostriatal dopaminergic system of the rat. For this purpose, Wistar rat litters were culled to 8 pups, retaining preferentially 4 males and 4 females, which, in the day following birth (postnatal day 1, PND1), were randomly attributed to either the Meth or control group. Meth-groups were administered 10 mg of (+)-methamphetamine hydrochloride/kg body weight/day, subcutaneously, twice daily, from PND1 until PND29; control groups received isovolumetric doses of saline. Animals were sacrificed at PND30. Males exposed to Meth during the first month of life had increased tyrosine hydroxylase (TH) activity both in the caudate-putamen and substantia nigra. Males also had increased nigral TH mRNA levels, as assessed by in situ hybridization. These effects did not exist in females. These results support the evidence that Meth exposure during the first month of life in the rat has a gender-specific stimulatory effect upon the maturation of TH, the key enzyme for dopamine biosynthesis in the nigrostriatal dopaminergic system.