Postnatal inorganic lead exposure reduces midbrain dopaminergic impulse flow and decreases dopamine D1 receptor sensitivity in nucleus accumbens neurons

J Pharmacol Exp Ther. 2005 Mar;312(3):1280-8. doi: 10.1124/jpet.104.076166. Epub 2004 Nov 18.


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 mug/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 D(1) 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 D(1) 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 D(1) receptor sensitivity postsynaptically in the nucleus accumbens.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / pharmacology
  • Animals
  • Apomorphine / pharmacology
  • Growth / drug effects
  • Haloperidol / pharmacology
  • Immunohistochemistry
  • Lead / blood
  • Lead / toxicity*
  • Male
  • Mesencephalon / drug effects*
  • Mesencephalon / physiology
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / drug effects*
  • Tyrosine 3-Monooxygenase / analysis
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / physiology


  • Receptors, Dopamine D1
  • Lead
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
  • Tyrosine 3-Monooxygenase
  • Haloperidol
  • Apomorphine