Effect of postnatal iron administration on MPTP-induced behavioral deficits and neurotoxicity: behavioral enhancement by L-Dopa-MK-801 co-administration.
Two experiments were performed to investigate the interactive effects of postnatal iron administration and adult MPTP treatment upon the function of C57 Bl/6 mice tested at adult age and to ascertain the possible ameliatory effects of a subthreshold dose of L-Dopa co-administered with different doses of the uncompetitive glutamate antagonist, MK-801. Experiment I indicated that postnatal iron induced marked deficits (hypoactivity), initially, in all three parameters of motor activity at the 5.0 and 7.5 mg/kg doses, and to a lesser extent at the 2.5 mg/kg dose. Later combination with MPTP (2x40 mg/kg) potentiated severely these deficits. During the final period of testing a marked hyperactivity was obtained for the two higher dose groups; this effect was abolished in mice administered MPTP. Experiment II indicated that the deficits in motor activity parameters induced by postnatal iron at 7.5 mg/kg were alleviated in a dose-related manner by the co-administration of the uncompetitive glutamate antagonist, MK-801, with a subthreshold dose of L-Dopa. Postnatal iron (7.5 mg/kg) administration followed by low doses of MPTP (2x20 mg/kg) 3 months later virtually abolished all motor activity. The combination of these compounds increased also the motor activity of mice treated with MPTP (2x20 mg/kg) or mice treated with the combination of postnatal iron and MPTP. The combination of MK-801 with L-Dopa increased locomotor (0.3 mg/kg), rearing (0.1 and 0.3 mg/kg) and total activity (0.3 mg/kg) of iron-treated mice during the initial, hypoactive 30-min period of testing. Locomotor activity (0.1 mg/kg) of MPTP-treated mice was increased too during this period. During the final 30-min period of testing all three parameters of activity (locomotion, 0.3 mg/kg; rearing and total activity, 0.1 and 0.3 mg/kg) were enhanced in the iron-treated mice, locomotion (0.1 mg/kg) and rearing (0.1 mg/kg) in the iron plus MPTP treated mice and only locomotion (0.1 mg/kg) in the MPTP-treated mice. In control mice (vehicle+saline), the higher doses of MK-801 (0.1 and 0.3 mg/kg) enhanced both locomotor and total activity. Analyses of total iron concentration in the frontal cortex and basal ganglia of Fe(2+) and vehicle treated mice indicated that marked elevations basal ganglia iron levels of the 5.0 and 7.5 mg/kg groups, later injected either saline or MPTP, were obtained (Experiment I). In Experiment II, iron concentrations in the basal ganglia were elevated in both the Fe(2+)-sal and Fe(2+)-MPTP groups to 170 and 177% of Veh.-sal values, respectively. There was a significant increase in the frontal cortex of iron-treated mice later administered either saline or MPTP (2x40 mg/kg) in Experiment I as well as in those given iron followed by MPTP (2x20mg/kg) in Experiment II. The implications of iron overload in parkinsonism seem confirmed by the interactive effects of postnatal administration of the metal followed by adult MPTP treatment upon motor activity and the activity-enhancing effects of co-administration of L-Dopa with MK-801.
Fredriksson
Anders
A
Department of Neuroscience and Psychiatry, University of Uppsala, Ulleråker, SE-750 17, Uppsala, Sweden.
Archer
Trevor
T
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D003423:Critical Period, Psychological; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D007501:Iron / Q000032:analysis / Q000633:toxicity*; D019190:Iron Overload / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D007980:Levodopa / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D020267:MPTP Poisoning / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D013995:Time
D015259:Dopamine Agents; D018696:Neuroprotective Agents; D007980:Levodopa; D016291:Dizocilpine Maleate; D007501:Iron