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NEUROPHARMACOLOGY

Postnatal Inorganic Lead Exposure Reduces Midbrain Dopaminergic Impulse Flow and Decreases Dopamine D1 Receptor Sensitivity in Nucleus Accumbens Neurons

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan

Lead treatment via drinking water for 3 to 6 weeks at 250 ppm was found to significantly decrease the number of spontaneously active dopamine (DA) neurons in both the substantia nigra and ventral tegmental area that were recorded using standard extracellular electrophysiological recording techniques. Lead exposure did not affect the discharge rate or discharge pattern of these DA neurons. No significant decrease in the number of tyrosine hydroxylase immunopositive cells was detected in lead-treated animals relative to controls even though the length of lead exposure was extended beyond that of the electrophysiological studies. The significant lead-induced decrease in spontaneously active cells observed in the electrophysiological studies was, therefore, not due to cell death. An acute drug challenge with the DA receptor agonist apomorphine at a dose known to hyperpolarize midbrain DA neurons (50 µg/kg i.v.) was used to determine whether hyperpolarization would normalize the number of spontaneously active DA neurons. The results suggest that depolarization inactivation was most likely not the cause for this lead effect. The D₁ receptor agonist SKF-38393 [1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol] was iontophoretically applied to type I nucleus accumbens (Nacb) neurons. The results demonstrated that type I Nacb neurons have a significantly lower basal discharge rate in lead-treated animals relative to controls and that the Nacb DA D₁ receptors were significantly less sensitive to SKF-38393 in the lead-treated animals. Therefore, lead exposure decreases DA neuron impulse flow presynaptically and decreases DA D₁ receptor sensitivity postsynaptically in the nucleus accumbens.

Address correspondence to: Dr. David K. Pitts, Dept. Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48202. E-mail: pitts{at}wayne.edu