Regulation of dopaminergic activity, but not tyrosine hydroxylase, is diminished after chronic inorganic lead exposure.

Previous work has indicated that the neurotoxic action of environmentally relevant levels of lead (Pb) on dopaminergic neurons is primarily presynaptic in nature and related to impaired regulation of dopamine (DA) synthesis and decreased DA release. This study was conducted to assess the functional integrity of the regulation of DA synthesis in caudate-putamen (C-P) and nucleus accumbens (NAc) of chronically Pb-exposed rats by measuring tyrosine hydroxylase (TH) activity. A pharmacological paradigm was employed that isolated autoreceptor-mediated regulation of the enzyme. At parturition dams received 0.2% Pb acetate (1090 ppm) in the drinking water while control dams received distilled water. Offspring were weaned to and maintained on the same solution given their dams until termination at 60 or 120 days. Rats were given saline or one of three DA agonists (EMD 23448, CGS 15855A, TL-99) 45 or 60 min before termination followed 15 min later by 750 mg/kg i.p. of gamma-butyrolactone (GBL) or saline. The ability of a DA agonist to prevent the GBL-induced increase in DA content was significantly altered in C-P of exposed rats compared to controls. No effect of Pb on DA content was observed in NAc. Furthermore, no differences in the ability of DA agonists to inhibit GBL-induced activation of TH in Pb-exposed compared to control animals were apparent in either brain region at either age by use of the tritium release method or the accumulation of L-DOPA. On the other hand, concentrations of DA metabolites in exposed rats given GBL and EMD 23448 were significantly lower than those in controls in both C-P and NAc. These findings support previous work suggesting that chronic Pb has multiple actions on CNS dopaminergic neurons consisting of impaired regulation of DA content and decreased DA release. However, these effects cannot be attributed to alterations in autoreceptor-mediated regulation of TH activity.