Diminished regulation of mesolimbic dopaminergic activity in rat after chronic inorganic lead exposure.
Previous studies in this laboratory have indicated that chronic lead (Pb) exposure during development induces a neurotoxicity in dopamine (DA) neurons that is primarily presynaptic in nature and at least partially related to altered regulation of DA synthesis. A primary form of DA synthesis regulation is the inhibition exerted on synaptic tyrosine hydroxylase activity via dopaminergic autoreceptors. This study assessed the functional status of this mechanism in Pb-exposed rats employing a pharmacological model. 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 125 days. Rats were given saline or 6,7-dihydroxy-2-dimethylaminotetralin (TL-99, 2.5-20 mg/kg ip) 40 min before termination followed 10 min later by 750 mg/kg ip of gamma-butyrolactone (GBL) or saline. The ability of TL-99 to prevent the GBL-induced increase in DA content was significantly diminished in nucleus accumbens (NAc) of exposed rats compared to controls, indicating that chronic Pb impairs receptor-mediated regulation of DA synthesis in mesolimbic neurons. No effect of Pb was observed in caudate-putamen. In animals receiving only saline injections concentrations of the DA metabolites, homovanillic acid and dihydroxyphenylacetic acid, were significantly decreased by Pb in the range of 17-31% and 12-24%, respectively. DA content was also significantly diminished by Pb in ventral tegmental area of these latter groups. These findings suggest that chronic Pb has multiple actions on central nervous system dopaminergic neurons consisting of an impaired regulation of DA synthesis that is apparently independent of a decrease in DA release.
Lasley
S M
SM
Department of Basic Sciences, University of Illinois College of Medicine, Peoria 61656.
Lane
J D
JD
D015107:4-Butyrolactone / Q000494:pharmacology; D000818:Animals; D004298:Dopamine / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D007854:Lead / Q000032:analysis / Q000633:toxicity*; D008032:Limbic System / Q000187:drug effects*; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; D007854:Lead; C016893:2-(N,N-dimethylamino)-6,7-dihydroxytetralin; D015107:4-Butyrolactone; D004298:Dopamine