Effects of MAO inhibitors upon MPTP mice chronically treated with suprathreshold doses of l -dopa

Abstract

Groups of mice were administered either saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (2 × 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 α-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.