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 inte rval) 4-6 weeks prior to behavioural testing. At testing, all the MPTP-inje cted mice were repeatedly administered L-dopa (20 mg/kg, s.c., five times e ach week, Monday-Friday), by applying a procedure that induced a severe red uction of motor activity parameters from Day 1 to Day 25. Control (uninject ed mice) received only saline and were retained only fur neurochemical anal ysis. In each of three experiments, following the reduction of the activity -stimulating effects of L-dopa by repeated administration, a restorative ef fect of different monoamine oxidase (MAO) inhibitors was tested by co-admin istration of the test compounds (irreversible MAO-B inhibitor, reversible M AO-A inhibitors, or irreversible MAO-A/mixed MAO inhibitors) with L-dopa (2 0 mg/kg). In each case the MAO inhibitor was injected 60 min prior to L-dop a. 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-dop a-tolerant mice. The reversible MAO-A inhibitors, amiflamine acid alpha -et hyltryptamine, in combination with L-dopa, reinstated locomotion and total activity, leaving rearing unaffected; Ro 41-1049 (3 mg/kg, s.c.) restored a ll three parameters of activity; locomotor activity was restored by all thr ee doses (1, 3, and 10 mg/kg, s.c.). On the other hand, neither the irrever sible MAO-A inhibitor, clorgyline, nor the mixed MAO inhibitor, phenelzine, produced any directly effective restorative increments. Neurochemical anal ysis confirmed the severe striatal dopamine depletion of MPTP-treated mice. These results demonstrate a synergistic and restorative action of combinin g certain MAO inhibitors, namely the reversible MAO-A inhibitors, with the suprathreshold dose of L-dopa in MPTP-treated, L-dopa-tolerant mice. (C) 20 00 Lippincott Williams & Wilkins.