Effects of MAO inhibitors upon MPTP mice chronically treated with suprathreshold doses of L-dopa.
Groups of mice were administered either saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (2 X 40 mg / kg, s.c., separated by a 24-hour interval) 4-6 weeks prior to behavioural testing. At testing, all the MPTP-injected mice were repeatedly administered L-dopa (20 mg / kg, s.c., five times each week, Monday-Friday), by applying a procedure that induced a severe reduction of motor activity parameters from Day 1 to Day 25. Control (uninjected mice) received only saline and were retained only for neurochemical analysis. In each of three experiments, following the reduction of the activity-stimulating effects of L-dopa by repeated administration, a restorative effect of different monoamine oxidase (MAO) inhibitors was tested by co-administration of the test compounds (irreversible MAO-B inhibitor, reversible MAO-A inhibitors, or irreversible MAO-A / mixed MAO inhibitors) with L-dopa (20 mg / kg). In each case the MAO inhibitor was injected 60 min prior to L-dopa. L-Deprenyl (3 or 10 mg / kg, s.c.), in combination with L-dopa, reinstated locomotion and total activity, but not rearing, dose-dependently, in L-dopa-tolerant mice. The reversible MAO-A inhibitors, amiflamine and alpha-ethyltryptamine, in combination with L-dopa, reinstated locomotion and total activity, leaving rearing unaffected; Ro 41-1049 (3 mg / kg, s.c.) restored all three parameters of activity; locomotor activity was restored by all three doses (1, 3, and 10 mg / kg, s.c.). On the other hand, neither the irreversible MAO-A inhibitor, clorgyline, nor the mixed MAO inhibitor, phenelzine, produced any directly effective restorative increments. Neurochemical analysis confirmed the severe striatal dopamine depletion of MPTP-treated mice. These results demonstrate a synergistic and restorative action of combining certain MAO inhibitors, namely the reversible MAO-A inhibitors, with the suprathreshold dose of L-dopa in MPTP-treated, L-dopa-tolerant mice.
Fredriksson
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Department of Psychiatry, University of Uppsala, Sweden
Palomo
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Archer
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D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003010:Clorgyline / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007980:Levodopa / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D010624:Phenelzine / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D012642:Selegiline / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology
D015259:Dopamine Agents; D008996:Monoamine Oxidase Inhibitors; D010627:Phenethylamines; D013844:Thiazoles; D014363:Tryptamines; D012642:Selegiline; C063456:Ro 41-1049; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C038034:etryptamine; D003010:Clorgyline; C031466:amiflamine; D010624:Phenelzine; D004298:Dopamine