Magnitude and duration of hyperactivity following neonatal 6-hydroxydopamine is related to the extent of brain dopamine depletion

Abstract

This experiment examined the relationship between the extent of brain dopamine (DA) neuron destruction in the neonatal rat and locomotor hyperactivity during subsequent development. Brain DA neurons were destroyed selectively in neonatal rats by intraventricular injections of 6-hydroxydopamine (6-OHDA) following desmethylimipramine (DMI) pretreatment of both days 3 and 6 of life. Groups of rats received total doses of 50, 70, 100 or 200 microgram of 6HDA or the vehicle solution. Each group of rats given 6-OHDA displayed 3- to 5-fold increases in locomotor activity relative to vehicle control rats on days 16 and 18 of life. Rats given 50 or 70 microgram of 6-OHDA displayed hyperactivity that diminished during days 18-32 of life, approaching the level of activity seen in vehicle-treated rats. It contrast, rats given 100 or 200 microgram of 6-OHDA displayed consistently high levels of locomotion during days 18-32 of life. When tested as adults (days 55-66 of life) only those rats given 200 micrograms of 6-OHDA as neonates continued to display locomotor hyperactivity. The extent of 6-OHDA-induced depletion of DA was proportional to the magnitude of locomotor hyperactivity seen during neonatal life. Brain DA was depleted to the greatest extent in rats which displayed permanent hyperactivity. Regardless of the extent of depletion of brain DA, adult rats given intraventricular injections of 125, 200 or 275 micrograms of 6-OHDA at 48 days of age (following pargyline and DMI pretreatment) displayed no significant change in locomotor activity. These results indicate that the magnitude and duration of locomotor hyperactivity seen following neonatal 6-OHDA injections are correlated with the extent of loss of central DA neurons and suggest that brain DA projections exert important influences on the ontogeny of normal locomotion.