TY - JOUR T1 - Postnatal Inorganic Lead Exposure Reduces Midbrain Dopaminergic Impulse Flow and Decreases Dopamine D1 Receptor Sensitivity in Nucleus Accumbens Neurons JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1280 LP - 1288 DO - 10.1124/jpet.104.076166 VL - 312 IS - 3 AU - Mahboubeh Tavakoli-Nezhad AU - David K. Pitts Y1 - 2005/03/01 UR - http://jpet.aspetjournals.org/content/312/3/1280.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -