Neonatal 6-hydroxydopamine-induced hypo/hyperactivity: blockade by dopamine reuptake inhibitors and effect of acute D-amphetamine

Five experiments were performed to assess the changes in motor activity resulting from neonatal administration of 6-hydroxydopamine (6-OHDA) on Days 1 or 2 postnatal, at doses of either 75 or 100 μg in a volume of 10 μl vehicle, following pretreatment with either GBR 12909 (40 mg/kg, s.c.) or amphonelic acid (4.0 mg/kg, s.c.) or saline. Motor activity was measured either over 60-min test periods on five consecutive days of testing or at 12-min intervals within a single 60-min test session. The initial extent of locomotor hyperactivity was dependent upon the neonatal dose of 6-OHDA: the 100 μg, but not 75 μg, dose induced marked hyperactivity from test day 1 onwards whereas the 75 μg dose did so from test day 3 onwards. The initial hypoactivity for rearing behaviour was observed for both doses of 6-OHDA: this hypoactivity was altered over successive test days so that by test day 5 an hyperactivity by the 75 μg, but not 100 μg, was observed. Pretreatment with either GBR 12909 or amphonelic acid abolished the effects of both doses of 6-OHDA. In the within 60-min test session procedure, 6-OHDA treated rats (both 75 and 100 μg) showed initial hyperactivity for locomotion that intensified, in relation to the other groups, over each 12-min interval and initial hypoactivity for rearing that developed into hyperactivity over each 12-min interval. Pretreatment with either GBR 12909 or amphonelic acid again abolished the effects of both doses of 6-OHDA (75 and 100 μg) rats, compared to the control groups in all four experiments. In Experiment V, a low dose of D-amphetamine abolished the hyperactivity of 6-OHDA (75μg) treated rats whereas a higher dose did so only transiently. Pretreatment with GBR 12909 abolished these effects. These findings underline the neuropharmacological utility of the neonatal 6-OHDA treatment for studying brain receptor system adaptive changes underlying the respective functional alterations and as a possible laboratory model for clinical disorders.