Effects of 6-hydroxydopa on noradrenergic neurons in developing rat brain

The temporal sequence of changes in norepinephrine (NE) levels in various regions of brains of control and 6-hydroxydopa (6-OHDOPA)-treated rats was determined. It was found that 6-OHDOPA (60 mug/g i.p., three doses, 48-hour intervals), when administered from birth, markedly altered the NE content of various brain regions during the following 8-week period. In telencephalic regions, such as the neocortex and hippocampus, NE levels (micrograms per tissue) increased dramatically from birth in saline-treated rats, while NE was depressed by 55 to 85% in 6-OHDOPA animals. Studies for measuring the uptake of 3H-NE (2 X 10(-7) M) by synaptosomes isolated from the neocortex showed that uptake, was reduced by approximately 40% at 2, 5 and 52 weeks of age. Therefore, it appears that 6-OHDOPA is able to permanently impair the ontogenetic development of noradrenergic neurons in regions supplied by the dorsal noradrenergic bundle. In contrast to these effects, NE levels in the cerebellum were elevated 2-fold in 6-OHDOPA-treated rats of 8 weeks, postnatal age. Uptake was not similarly increased, indicating that the elevation in NE was not due to an increase in the number of nerve endings, but rather to an increase in the intraneuronal storage depots of NE. In the hypothalamus NE levels were not dramatically altered, while uptake was reduced by about 40% up to 1 year of age. Application of Michaelis-Menten kinetics indicated a decrease in the Vmax for 3H-NE uptake in the hypothalamus of 6-OHDOPA (60 mug/g i.p., two doses, 48-hour intervals from birth)-treated rats, sacrificed at 6 months of age. The pons-medulla and midbrain regions showed moderate increases in NE levels at 5 and 8 weeks. Uptake 1 was not increased in the pons-medulla at any time, and the Vmax remained unchanged when measured in rats at 6 months of age. It is apparent that 6-OHDOPA is capable of altering the ontogenesis of noradrenergic neurons and that the effects on development are different in different areas of the brain.