Substantial evidence indicates that lead (Pb) has a significant developmental impact on the midbrain dopaminergic (DA) system, and suggests that this system can be affected at low levels of exposure. Since the DA system is thought to play a role in cognition, attention, learning, and motor behavior, a role of the DA system in the neurotoxic effects of Pb is consistent with the neurological profile observed following childhood Pb exposure. Neurochemical reports have indicated that Pb alters DA turnover, DA release and the development of postsynaptic DA receptors. However, very little is known about the consequences of postnatal exposure on the dopaminergic system at the cellular level in vivo. The absence of any information concerning the effects of Pb on impulse generation in DA neurons or DA neuron viability represents a serious gap in our understanding of the impact of Pb on the DA system. The proposed experiments will examine the electrophysiological activity of the midbrain DA-containing neurons and target neurons in the striatum and nucleus accumbens by using single-cell electrophysiological recording techniques. In addition, immuno-histochemical techniques and specific behavioral assays will be used to examine the impact of Pb on DA neuron survival and the behaviors modulated by the DA system respectively. This approach will provide a thorough analysis of DA neuronal activity and provide the ability to correlate electrophysiological, immuno-histochemical and behavioral findings with blood and brain Pb levels. Two different exposure protocols will be used. In the pre-weaning protocol Pb will be provided to offspring via the milk of lactating dams that consume Pb-treated drinking water. In the post-weaning protocol Pb will be provided directly to weanlings via their drinking water. The overall hypothesis is that postnatal Pb exposure alters the electrophysiological activity and/or survival of midbrain DA neurons. The effects on the presynaptic component of the DA system (i.e., DA neurons) may then have an impact on the postsynaptic component, and this would be seen as changes in postsynaptic DA receptor responses and specific DA-related behaviors. Results obtained from these studies will be relevant to our understanding of the impact of low level Pb exposure on human brain development, and will provide more detailed insight into the neurological problems associated with such exposure at the cellular level.
| Tavakoli-Nezhad, Mahboubeh; Pitts, David K (2005) Postnatal inorganic lead exposure reduces midbrain dopaminergic impulse flow and decreases dopamine D1 receptor sensitivity in nucleus accumbens neurons. J Pharmacol Exp Ther 312:1280-8 |
| Lewis, Mark W; Pitts, David K (2004) Inorganic lead exposure in the rat activates striatal cFOS expression at lower blood levels and inhibits amphetamine-induced cFOS expression at higher blood levels. J Pharmacol Exp Ther 310:815-20 |
| Tavakoli-Nezhad, M; Barron, A J; Pitts, D K (2001) Postnatal inorganic lead exposure decreases the number of spontaneously active midbrain dopamine neurons in the rat. Neurotoxicology 22:259-69 |
