Chronic levodopa impairs morphological development of grafted embryonic dopamine neurons

Degeneration and plasticity of dopamine (DA) neurons may be influenced by their own neurotransmitter and/or metabolic by-products. Substances with known neurotoxic properties, such as hydrogen peroxide and 6-hydroxydopamine, are produced during oxidation of DA. Additionally, DA can directly regulate neurite outgrowth in both invertebrate and vertebrate species. We have begun to investigate the influence of increased local transmitter concentrations on the morphological plasticity of neurons by examining the effect of chronic levodopa, a drug that increases DA synthesis, on grafted embryonic nigral DA neurons in a rat model of experimental parkinsonism and in monolayer cell cultures. Results from our in vivo investigation show that although chronic levodopa does not significantly affect the number of surviving grafted cells, morphological development of these embryonic DA neurons appears impaired. Levodopa administered chronically to fetal DA neurons in culture results in a decreased number of surviving neurons as well as a reduction in neurite outgrowth with increasing concentration of levodopa ranging from 10(-8) to 10(-4) M. This information provides further evidence to support the hypothesis that excess DA or its metabolites can influence the survival and growth of DA neurons. These results may be important in the design of pharmacotherapy for Parkinson's disease and the combination of drug and neural grafting therapies in this disorder.