Effects of neonatal exposure to methamphetamine: catecholamine levels in brain areas of the developing rat.

Neonatal exposure to moderate doses of methamphetamine during the first month of life in the rat affects tyrosine hydroxylase gene expression in the substantia nigra and nigrostriatal tyrosine hydroxylase activity. The main goal of this work was to evaluate the ontogeny of the neurochemical effects of repeated exposure to moderate doses of methamphetamine during the first month of life in the rat. Norepinephrine, dopamine, and dihydroxyphenylacetic acid levels were measured in target areas of methamphetamine: the substantia nigra, ventral tegmental area, caudate-putamen, nucleus accumbens, and medial prefrontal cortex. On postnatal day 1 (PND1), Wistar rat litters, culled to eight pups, sex balanced, were randomly attributed to either methamphetamine or control groups. Methamphetamine groups were administered 10 mg of (+/-)-methamphetamine/kg body weight/day, subcutaneously, from PND1 until the day prior to sacrifice; control groups received isovolumetric saline. Groups were sacrificed on PND7, PND14, and PND30. Neonatal methamphetamine exposure increased norepinephrine levels in the substantia nigra of PND30 rats; on PND14, this variation was evident only in male pups. In the substantia nigra, the dihydroxyphenylacetic/dopamine ratio was also affected in PND30 males. In the ventral tegmental area, catecholamine levels were not affected by methamphetamine. Norepinephrine levels were also increased in the caudate-putamen of PND7 male and PND14 female methamphetamine-exposed pups and in the nucleus accumbens of PND14 female and PND30 male and female pups. Catecholamine levels in the medial prefrontal cortex were not affected by neonatal methamphetamine administration.

Prenatal exposure to methamphetamine in the rat: ontogeny of tyrosine hydroxylase mRNA expression in mesencephalic dopaminergic neurons.

Methamphetamine (Meth) is an illicit substance known to interfere with catecholaminergic systems and a popular recreational drug among young adult women, that is, in gestational age. Tyrosine hydroxylase (TH), the rate-limiting enzyme of the synthetic pathway of catecholamines, is a good marker to assess potential effects of Meth in catecholaminergic (particularly in dopaminergic) systems. In the rat, prolonged neonatal Meth exposure altered several dopaminergic markers (TH activity and gene expression) in substantia nigra pars compacta (SN) and in caudate-putamen (TH activity) when animals matured. However, it was never verified whether gestational exposure to Meth might compromise TH enzyme in the pups during the neonatal immature periods. The present study was designed to address this issue by analyzing TH gene expression, measured by in situ hybridization in SN and ventral tegmental area (VTA), dopaminergic areas that are well characterized as target areas for Meth, and in rats prenatally exposed to this psychostimulant. To this end, dated pregnant Wistar rat dams received 5 mg Meth hydrochloride/kg body weight/day. It was administered subcutaneously from gestational day 8 until 22. The control group was pair-fed and saline injected, using the same experimental protocol as for Meth-treated dams. On the day of birth (postnatal day 0, PND 0), litters were culled to 8 pups, sex-balanced whenever possible, and were followed until the day of sacrifice (PND 7, 14, or 30). Meth treatment differentially affected TH mRNA levels in VTA and SN, in an age- and gender-dependent manner. Thus, TH mRNA levels were decreased in the VTA of PND 7 and PND 14 females gestationally exposed to Meth; this effect was not evident in males or on PND 30. TH mRNA levels also tend to decrease in SN of PND 14 females gestationally exposed to Meth. Collectively, the present results indicated that gestational Meth exposure affects TH gene expression in the postnatal life, a phenomenon that appears to be transient, since it is no longer evident by the end of the first month of life in the rat.