Previous studies have demonstrated that postnatal (days 2-29 of life) administration of lead (200 mg/kg/day by gavage) to Long-Evans rats caused permanent increases in lithium-induced polydipsia (LIP)12. These lead-induced increases in LIP were apparently not of renal origin, did not occur in animals treated with lead after day 30, and persisted for at least 6 months12,13. The present studies have narrowed the dose-time window for lead-induced increases in LIP. The first study showed that continuous administration of lead (200 mg/kg/day, p.o.) in the form of lead acetate during days 2-9 of life caused increases in LIP (P = 0.022). Although lead-induced increases in LIP were not statistically significant (P = 0.084) for the group administered lead from days 9 to 19, the lack of a significant difference between the 2-9- and 9-19-day groups suggested that lead treatment during either of these time periods would result in LIP increases. Lead administration between days 19 and 29 of life was not effective in increasing LIP (P = 0.8). In the second study, a single dose of lead (200 mg/kg/day) was administered either on day 5 or 15 of life. Concentrations of lead in the blood on day 30 of life averaged 23.2 μg/100 ml for treated rats versus 4.8 μg/100 ml for controls. When tested at approximately 90 days of age, both groups showed significant increases in LIP (P = 0.028). The rats from this second study were also examined for changes in nigrostriatal dopamine function, since this pathway is known to be essential for LIP14. After washout of lithium, no differences in the Kd or Bmax of [3H]spiperone binding were observed between lead-treated and control groups (P > 0.4). There were also no differences in the concentrations of dopamine and its acidic metabolites DOPAC and HVA, nor in the ratios of DOPAC or HVA to dopamine (P > 0.4). Thus, rats with permanent changes in pharmacological sensitivity to lithium have no apparent differences in the characteristics of the unchallenged nigrostriatal dopamine pathway. Whether challenge with lithium should reveal latent differences in these parameters, or whether the nigrostriatal dopamine pathway is not the locus of lead-induced increases in LIP, remains to be determined. In either case, the permanent changes in LIP that may be caused by administration of a single, 200 mg/kg oral dose of lead during the first weeks of life is believed to represent the most sensitive index of lead-induced change in the CNS that has been documented. Since a defined pharmacological probe is used, this should permit elucidation of the involved mechanism(s).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Clinical Neurology
- Developmental Biology